Compositions comprising bacterial strains

ABSTRACT

The invention provides compositions comprising bacterial strains for treating and preventing inflammatory and autoimmune diseases.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Nov. 22, 2016, isnamed 49455_712_201_P067606XX_sequence_listing.txt and is 7,863 bytes insize.

CROSS REFERENCE

This application is a divisional application of U.S. application Ser.No. 15/359,972, filed on Nov. 23, 2016; which claims priority to GBApplication No. 1520638.6, filed on Nov. 23, 2015, each of which areherein incorporated by reference in their entirety.

TECHNICAL FIELD

This invention is in the field of compositions comprising bacterialstrains isolated from the mammalian digestive tract and the use of suchcompositions in the treatment of disease.

BACKGROUND TO THE INVENTION

The human intestine is thought to be sterile in utero, but it is exposedto a large variety of maternal and environmental microbes immediatelyafter birth. Thereafter, a dynamic period of microbial colonization andsuccession occurs, which is influenced by factors such as delivery mode,environment, diet and host genotype, all of which impact upon thecomposition of the gut microbiota, particularly during early life.Subsequently, the microbiota stabilizes and becomes adult-like [1]. Thehuman gut microbiota contains more than 500-1000 different phylotypesbelonging essentially to two major bacterial divisions, theBacteroidetes and the Firmicutes [2]. The successful symbioticrelationships arising from bacterial colonization of the human gut haveyielded a wide variety of metabolic, structural, protective and otherbeneficial functions. The enhanced metabolic activities of the colonizedgut ensure that otherwise indigestible dietary components are degradedwith release of by-products providing an important nutrient source forthe host. Similarly, the immunological importance of the gut microbiotais well-recognized and is exemplified in germfree animals which have animpaired immune system that is functionally reconstituted following theintroduction of commensal bacteria [3-5].

Dramatic changes in microbiota composition have been documented ingastrointestinal disorders such as inflammatory bowel disease (IBD). Forexample, the levels of Clostridium cluster XIVa bacteria are reduced insubjects with IBD whilst numbers of E. coli are increased, suggesting ashift in the balance of symbionts and pathobionts within the gut [6-9].Interestingly, this microbial dysbiosis is also associated withimbalances in T effector cell populations.

In recognition of the potential positive effect that certain bacterialstrains may have on the animal gut, various strains have been proposedfor use in the treatment of various diseases (see, for example,[10-13]). Also, certain strains, including mostly Lactobacillus andBifidobacterium strains, have been proposed for use in treating variousinflammatory and autoimmune diseases that are not directly linked to theintestines (see [14] and [15] for reviews). However, the relationshipbetween different diseases and different bacterial strains, and theprecise effects of particular bacterial strains on the gut and at asystemic level and on any particular types of diseases, are poorlycharacterized.

Cell wall fragments from Streptococcus pyogenes, Lactobacillus casei andvarious strains of Eubacterium, including E. contortum, have been foundto induce chronic polyarthritis and joint inflammation (see [16]).

There is a requirement in the art for new methods of treatinginflammatory and autoimmune diseases. There is also a requirement forthe potential effects of gut bacteria to be characterized so that newtherapies using gut bacteria can be developed.

SUMMARY OF THE INVENTION

The inventors have developed new therapies for treating and preventinginflammatory and autoimmune diseases. In particular, the inventors havedeveloped new therapies for treating and preventing diseases andconditions mediated by IL-17 or the Th17 pathway. In particular, theinventors have identified that bacterial strains from the genusEubacterium can be effective for treating and preventing diseases andconditions mediated by IL-17 or the Th17 pathway. As described in theexamples, oral administration of compositions comprising Eubacteriumcontortum may reduce the severity of the inflammatory response,including the Th17 inflammatory response, in mouse models of uveitis.

Therefore, in a first embodiment, the invention provides a compositioncomprising a bacterial strain of the genus Eubacterium, for use in amethod of treating or preventing a disease or condition mediated byIL-17 or the Th17 pathway. The inventors have identified that treatmentwith bacterial strains from this species can provide clinical benefitsin mouse models of inflammatory and autoimmune diseases mediated byIL-17 and the Th17 pathway, may reduce levels of cytokines that are partof the Th17 pathway, including IL-17, and may alleviate the Th17inflammatory response.

In particular embodiments, the invention provides a compositioncomprising a bacterial strain of the genus Eubacterium, for use in amethod of treating or preventing a disease or condition selected fromthe group consisting of: uveitis; cancer, such as breast cancer, lungcancer, liver cancer, colon cancer, or ovarian cancer; multiplesclerosis; arthritis, such as rheumatoid arthritis, osteoarthritis,psoriatic arthritis, or juvenile idiopathic arthritis; neuromyelitisoptica (Devic's disease); ankylosing spondylitis; spondyloarthritis;psoriasis; systemic lupus erythematosus; inflammatory bowel disease,such as Crohn's disease or ulcerative colitis; celiac disease; asthma,such as allergic asthma or neutrophilic asthma; chronic obstructivepulmonary disease (COPD); scleritis; vasculitis; Behcet's disease;atherosclerosis; atopic dermatitis; emphysema; periodontitis; allergicrhinitis; and allograft rejection. The effect shown for the bacterialstrains from the genus Eubacterium on the Th17 inflammatory response andon diseases mediated by IL-17 and the Th17 pathway may providetherapeutic benefits for other diseases and conditions mediated by IL-17and the Th17 pathway, such as those listed above.

In particularly preferred embodiments, the invention provides acomposition comprising a bacterial strain of the genus Eubacterium, foruse in a method of treating or preventing uveitis, such as posterioruveitis. The inventors have identified that treatment with Eubacteriumstrains can reduce disease incidence and disease severity in a mousemodel of uveitis and can prevent or reduce retinal damage. In preferredembodiments, the invention provides a composition comprising a bacterialstrain of the species Eubacterium contortum, for use in the treatment ofuveitis. Compositions using Eubacterium contortum may be particularlyeffective for treating uveitis.

In further preferred embodiments, the invention provides a compositioncomprising a bacterial strain of the genus Eubacterium, for use in amethod of treating or preventing asthma, such as neutrophilic asthma orallergic asthma. Treatment with Eubacterium strains may reducerecruitment of neutrophils and eosinophils into the lungs, which canhelp treat or prevent asthma. In certain embodiments, the composition isfor use in a method of treating or preventing neutrophilic asthma oreosinophilic asthma. The compositions of the invention may beparticularly effective for treating or preventing neutrophilic asthmaand eosinophilic asthma. Indeed, in certain embodiments, the compositionis for use in a method of reducing a neutrophilic inflammatory responsein the treatment or prevention of asthma, or the composition is for usein a method of reducing an eosinophilic inflammatory response in thetreatment or prevention of asthma. In preferred embodiments, theinvention provides a composition comprising a bacterial strain of thespecies Eubacterium contortum for use in the treatment of asthma, and inparticular eosinophilic or allergic asthma. Also, Eubacterium contortummay have a particularly pronounced effect on neutrophils in asthmamodels and treatment with Eubacterium contortum may be particularlyeffective for treating neutrophilic asthma.

In further preferred embodiments, the invention provides a compositioncomprising a bacterial strain of the genus Eubacterium, for use in amethod of treating or preventing rheumatoid arthritis. Treatment withEubacterium strains may provide clinical benefits in a mouse model ofrheumatoid arthritis and reduce joint swelling. In preferredembodiments, the invention provides a composition comprising a bacterialstrain of the species Eubacterium contortum, for use in the treatment ofrheumatoid arthritis. Compositions using Eubacterium contortum may beparticularly effective for treating rheumatoid arthritis.

In further preferred embodiments, the invention provides a compositioncomprising a bacterial strain of the genus Eubacterium, for use in amethod of treating or preventing multiple sclerosis. Treatment withEubacterium strains may reduce disease incidence and disease severity ina mouse model of multiple sclerosis. In preferred embodiments, theinvention provides a composition comprising a bacterial strain of thespecies Eubacterium contortum, for use in the treatment of multiplesclerosis. Compositions using Eubacterium contortum may be particularlyeffective for treating multiple sclerosis.

In further preferred embodiments, the invention provides a compositioncomprising a bacterial strain of the genus Eubacterium, for use in amethod of treating or preventing cancer, such as breast, lung or livercancer. Compositions comprising a bacterial strain of the genusEubacterium may reduce tumor growth in mouse models of breast, lung andliver cancer. In certain embodiments, the composition is for use in amethod of reducing tumor size or preventing tumor growth in thetreatment of cancer. In certain embodiments, the invention provides acomposition comprising a bacterial strain of the species Eubacteriumcontortum, for use in the treatment of cancer.

In certain embodiments, the compositions of the invention are for use ina method of reducing IL-17 production or reducing Th17 celldifferentiation in the treatment or prevention of a disease or conditionmediated by IL-17 or the Th17 pathway. In particular, the compositionsof the invention may be used in reducing IL-17 production or reducingTh17 cell differentiation in the treatment or prevention of asthma,rheumatoid arthritis, multiple sclerosis, uveitis or cancer. Preferably,the invention provides compositions comprising a bacterial strain of thegenus Eubacterium contortum, for use in reducing IL-17 production orreducing Th17 cell differentiation in the treatment or prevention ofasthma, rheumatoid arthritis, multiple sclerosis, uveitis or cancer.

In certain embodiments, the composition is for use in a subject withelevated IL-17 levels or Th17 cells. The effect shown for Eubacteriumstrains on uveitis, which is strongly associated with the Th17inflammatory response, means that Eubacterium strains may beparticularly beneficial for such subjects.

In preferred embodiments of the invention, the bacterial strain in thecomposition is of Eubacterium contortum. Closely related strains mayalso be used, such as bacterial strains that have a 16s rRNA sequencethat is at least 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9% identical tothe 16s rRNA sequence of a bacterial strain of Eubacterium contortum.Preferably, the bacterial strain has a 16s rRNA sequence that is atleast 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9% identical to SEQ ID NO:1,2, 3 or 4. Preferably, the sequence identity is to SEQ ID NO:4.Preferably, the bacterial strain for use in the invention has the 16srRNA sequence represented by SEQ ID NO:4.

In certain embodiments, the composition of the invention is for oraladministration. Oral administration of the strains of the invention canbe effective for treating IL-17- or Th17 pathway-mediated diseases andconditions. Also, oral administration is convenient for patients andpractitioners and allows delivery to and/or partial or totalcolonization of the intestine.

In certain embodiments, the composition of the invention comprises oneor more pharmaceutically acceptable excipients, diluents, or carriers.

In certain embodiments, the composition of the invention comprises abacterial strain that has been lyophilized. Lyophilization is aneffective and convenient technique for preparing stable compositionsthat allow delivery of bacteria.

In certain embodiments, the composition comprises a bacterial strainthat has been lyophilized; and further comprises a pharmaceuticallyacceptable excipient, diluent, or carrier.

In certain embodiments, the composition comprises a lyoprotectant, whichcan be a pharmaceutically acceptable excipient, diluent, or carrier.

In certain embodiments, the composition is a lyophilized compositionwhich can be reconstituted prior to administration to a subject.

In certain embodiments, the invention provides a food product comprisingthe composition as described above.

In certain embodiments, the invention provides a vaccine compositioncomprising the composition as described above.

Additionally, the invention provides a method of treating or preventinga disease or condition mediated by IL-17 or the Th17 pathway, comprisingadministering a composition comprising a bacterial strain of the genusEubacterium.

In developing the above invention, the inventors have identified andcharacterized a bacterial strain that is particularly useful fortherapy. The Eubacterium contortum strain of the invention is shown tobe effective for treating the diseases described herein, such asuveitis. Therefore, in another aspect, the invention provides a cell ofthe Eubacterium contortum strain MRX050 (in particular MRX050 depositedas NCIMB 42689), or a derivative thereof. The invention also providescompositions comprising such cells, or biologically pure cultures ofsuch cells. The invention also provides a cell of Eubacterium contortumstrain MRX050 (in particular MRX050 deposited as NCIMB 42689), or aderivative thereof, for use in therapy, in particular for the diseasesdescribed herein.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference in their entirety forall purposes, to the same extent as if each individual publication,patent, or patent application was specifically and individuallyindicated to be incorporated by reference.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1: Mouse model of uveitis—TEFI Scores in the control group. Dataare presented as Mean±SEM.

FIG. 2: Mouse model of uveitis—TEFI Scores on Day 28. Data are presentedas Mean±SEM.

DETAILED DESCRIPTION Bacterial Strains

The compositions of the invention comprise a bacterial strain of thegenus Eubacterium. The examples demonstrate that bacteria of this genusare useful for treating or preventing uveitis and diseases andconditions mediated by IL-17 or the Th17 pathway. The preferredbacterial strains are of the species Eubacterium contortum.

The invention provides a Eubacterium, for example, a Eubacteriumcontortum for use in therapy, for example, for use in treating orpreventing an inflammatory and/or autoimmune disease. Similarly, theinvention provides a composition comprising a bacterial strain of thegenus Eubacterium, for example, a Eubacterium contortum, for use intherapy, for example, for use in treating or preventing an inflammatoryand/or autoimmune disease. In certain embodiments, the compositions ofthe invention comprise Eubacterium, for example, a Eubacteriumcontortum, and do not contain any other bacterial genus. In certainembodiments, the compositions of the invention comprise a single speciesof Eubacterium, for example, a Eubacterium contortum, and do not containany other bacterial species. In certain embodiments, the compositions ofthe invention comprise a single strain of Eubacterium, for example, ofEubacterium contortum and do not contain any other bacterial strains orspecies.

Examples of Eubacterium species for use in the invention includeEubacterium contortum, Eubacterium fissicatena, Eubacterium limosum,Eubacterium rectale and Eubacterium aerofaciens. Eubacterium are grampositive, obligately anaerobic, non-spore-forming rods which do notproduce propionic acid or lactic acid as a major acid product [17]. Thetype strain of Eubacterium contortum is ATCC 25540=DSM 3982 [17].GenBank accession numbers for the 16S rRNA gene sequence for Eubacteriumcontortum strain DSM 3982 are FR749945, FR749946 and L34615 (disclosedherein as SEQ ID NO:1-3). Exemplary Eubacterium contortum strains aredescribed in [17].

In some embodiments, the Eubacterium species for use in the invention isnot Eubacterium ventriosum. In some embodiments, the Eubacterium speciesfor use in the invention is not Eubacterium eligens. In someembodiments, a composition for use in the invention does not compriseEubacterium ventriosum. In some embodiments, a composition for use inthe invention does not comprise Eubacterium eligens.

All microorganism deposits were made under the terms of the BudapestTreaty. Maintenance of a viable culture is assured for 30 years from thedate of deposit. All restrictions on the availability to the public ofthe deposited microorganisms will be irrevocably removed upon thegranting of a patent for this application. The Eubacterium contortumbacterium tested in the Examples is referred to herein as strain MRX050.A 16S rRNA sequence for the MRX050 strain that was tested is provided inSEQ ID NO:4. Strain MRX050 was deposited with the internationaldepositary authority NCIMB, Ltd. (Ferguson Building, Aberdeen, AB21 9YA,Scotland) by 4D Pharma Research Ltd. (Life Sciences Innovation Building,Aberdeen, AB25 2ZS, Scotland) on 15th November 2016 and was assignedaccession number NCIMB 42689. The terms “MRX050” and “MRx0050” are usedinterchangeably herein.

Bacterial strains closely related to the strain tested in the examplesare also expected to be effective for treating or preventing uveitis anddiseases and conditions mediated by IL-17 or the Th17 pathway. Incertain embodiments, the bacterial strain for use in the invention has a16s rRNA sequence that is at least 95%, 96%, 97%, 98%, 99%, 99.5% or99.9% identical to the 16s rRNA sequence of a bacterial strain ofEubacterium contortum. Preferably, the bacterial strain for use in theinvention has a 16s rRNA sequence that is at least 95%, 96%, 97%, 98%,99%, 99.5% or 99.9% identical to SEQ ID NO:1, 2, 3 or 4. Preferably, thesequence identity is to SEQ ID NO:4. Preferably, the bacterial strainfor use in the invention has the 16s rRNA sequence represented by SEQ IDNO:4.

Bacterial strains that are biotypes of strains MRX050 (in particularMRX050 deposited as NCIMB 42689) and ATCC 25540 are also expected to beeffective for treating or preventing uveitis and diseases and conditionsmediated by IL-17 or the Th17 pathway. A biotype is a closely relatedstrain that has the same or very similar physiological and biochemicalcharacteristics.

Strains that are biotypes of strains MRX050 (in particular MRX050deposited as NCIMB 42689) or ATCC 25540 and that are suitable for use inthe invention may be identified by sequencing other nucleotide sequencesfor strains MRX050 (in particular MRX050 deposited as NCIMB 42689) orATCC 25540. For example, substantially the whole genome may be sequencedand a biotype strain for use in the invention may have at least 95%,96%, 97%, 98%, 99%, 99.5% or 99.9% sequence identity across at least 80%of its whole genome (e.g. across at least 85%, 90%, 95% or 99%, oracross its whole genome). For example, in some embodiments, a biotypestrain has at least 98% sequence identity across at least 98% of itsgenome or at least 99% sequence identity across 99% of its genome. Othersuitable sequences for use in identifying biotype strains may includehsp60 or repetitive sequences such as BOX, ERIC, (GTG)₅, or REP or [18].Biotype strains may have sequences with at least 95%, 96%, 97%, 98%,99%, 99.5% or 99.9% sequence identity to the corresponding sequence ofstrains MRX050 (in particular MRX050 deposited as NCIMB 42689) or ATCC25540. In some embodiments, a biotype strain has a sequence with atleast 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9% sequence identity to thecorresponding sequence of strain MRX050 deposited as NCIMB 42689 andcomprises a 16S rRNA sequence that is at least 99% identical (e.g. atleast 99.5% or at least 99.9% identical) to SEQ ID NO:4. In someembodiments, a biotype strain has a sequence with at least 95%, 96%,97%, 98%, 99%, 99.5% or 99.9% sequence identity to the correspondingsequence of strain MRX050 deposited as NCIMB 42689 and has the 16S rRNAsequence of SEQ ID NO:4.

Alternatively, strains that are biotypes of strains MRX050 (inparticular MRX050 deposited as NCIMB 42689) or ATCC 25540 and that aresuitable for use in the invention may be identified by using strainsMRX050 (in particular MRX050 deposited as NCIMB 42689) or ATCC 25540 andrestriction fragment analysis and/or PCR analysis, for example by usingfluorescent amplified fragment length polymorphism (FAFLP) andrepetitive DNA element (rep)-PCR fingerprinting, or protein profiling,or partial 16S or 23s rDNA sequencing. In preferred embodiments, suchtechniques may be used to identify other Eubacterium contortum strains.

In certain embodiments, strains that are biotypes of strains MRX050 (inparticular MRX050 deposited as NCIMB 42689) or ATCC 25540 and that aresuitable for use in the invention are strains that provide the samepattern as strains MRX050 (in particular MRX050 deposited as NCIMB42689) or ATCC 25540 when analyzed by amplified ribosomal DNArestriction analysis (ARDRA), for example when using Sau3AI restrictionenzyme (for exemplary methods and guidance see, for example,[19]).Alternatively, biotype strains are identified as strains that have thesame carbohydrate fermentation patterns as strains MRX050 (in particularMRX050 deposited as NCIMB 42689) or ATCC 25540.

Other Eubacterium contortum strains that are useful in the compositionsand methods of the invention, such as biotypes of strains MRX050 (inparticular MRX050 deposited as NCIMB 42689) or ATCC 25540, may beidentified using any appropriate method or strategy, including theassays described in the examples. For instance, strains for use in theinvention may be identified by culturing in anaerobic YCFA and/oradministering the bacteria to the type II collagen-induced arthritismouse model and then assessing cytokine levels. In particular, bacterialstrains that have similar growth patterns, metabolic type and/or surfaceantigens to strains MRX050 (in particular MRX050 deposited as NCIMB42689) or ATCC 25540 may be useful in the invention. A useful strainwill have comparable immune modulatory activity to strains MRX050 (inparticular MRX050 deposited as NCIMB 42689) or ATCC 25540. Inparticular, a biotype strain will elicit comparable effects on theuveitis disease models to the effects shown in the Examples, which maybe identified by using the culturing and administration protocolsdescribed in the Examples.

A particularly preferred strain of the invention is strain MRX050 strain(in particular MRX050 deposited as NCIMB 42689). This is the exemplarystrain tested in the examples and shown to be effective for treatingdisease. Therefore, the invention provides a cell, such as an isolatedcell, of Eubacterium contortum strain MRX050 (in particular MRX050deposited as NCIMB 42689), or a derivative thereof. The invention alsoprovides a composition comprising a cell of Eubacterium contortum strainMRX050 (in particular MRX050 deposited as NCIMB 42689), or a derivativethereof. The invention also provides a biologically pure culture ofEubacterium contortum strain MRX050 (in particular MRX050 deposited asNCIMB 42689). The invention also provides a cell of Eubacteriumcontortum strain MRX050 (in particular MRX050 deposited as NCIMB 42689),or a derivative thereof, for use in therapy, in particular for thediseases described herein. A derivative of Eubacterium contortum strainMRX050 (in particular MRX050 deposited as NCIMB 42689) may be a daughterstrain (progeny) or a strain cultured (subcloned) from the original.

A derivative of a strain of the invention may be modified, for exampleat the genetic level, without ablating the biological activity. Inparticular, a derivative strain of the invention is therapeuticallyactive. A derivative strain will have comparable immune modulatoryactivity to the Eubacterium contortum strain MRX050 (in particularMRX050 deposited as NCIMB 42689). In particular, a derivative strainwill elicit comparable effects on the uveitis disease models to theeffects shown in the Examples, which may be identified by using theculturing and administration protocols described in the Examples. Aderivative of strain MRX050 (in particular MRX050 deposited as NCIMB42689) will generally be a biotype of strain MRX050 (in particularMRX050 deposited as NCIMB 42689).

References to cells of Eubacterium contortum strain MRX050 encompass anycells that have the same safety and therapeutic efficacy characteristicsas strain MRX050, and such cells are encompassed by the invention.Reference to MRX050 deposited as NCIMB 42689 refers to the depositedMRX050 strain only.

In preferred embodiments, the bacterial strains in the compositions ofthe invention are viable and capable of at least partially or totallycolonizing the intestine.

Therapeutic Uses

As demonstrated in the examples, the bacterial compositions of theinvention are effective for reducing the Th17 inflammatory response. Inparticular, treatment with compositions of the invention achievesclinical improvements in animal models of conditions mediated by IL-17and the Th17 pathway and may achieve a reduction in IL-17A levels andother Th17 pathway cytokines. Therefore, the compositions of theinvention may be useful for treating or preventing inflammatory andautoimmune diseases, and in particular diseases or conditions mediatedby IL-17. In particular, the compositions of the invention may be usefulfor reducing or preventing elevation of the IL-17 inflammatory response.

Th17 cells are a subset of T helper cells that produce, for example,IL-17A, IL17-F, IL-21 and IL-22. Th17 cell differentiation and IL-17expression may be driven by IL-23. These cytokines and others formimportant parts of the Th17 pathway, which is a well-establishedinflammatory signaling pathway that contributes to and underlies anumber of inflammatory and autoimmune diseases (as described in, forexample, [20-25]). Diseases wherein the Th17 pathway is activated areTh17 pathway-mediated diseases. Th17 pathway-mediated diseases can beameliorated or alleviated by repressing the Th17 pathway, which may bethrough a reduction in the differentiation of Th17 cells or a reductionin their activity or a reduction in the level of Th17 pathway cytokines.Diseases mediated by the Th17 pathway may be characterized by increasedlevels of cytokines produced by Th17 cells, such as IL-17A, IL-17F,IL-21, IL-22, IL-26, IL-9 (reviewed in [26]). Diseases mediated by theTh17 pathway may be characterized by increased expression ofTh-17-related genes, such as Stat3 or IL-23R. Diseases mediated by theTh17 pathway may be associated with increased levels of Th17 cells.

IL-17 is a pro-inflammatory cytokine that contributes to thepathogenesis of several inflammatory and autoimmune diseases andconditions. IL-17 as used herein may refer to any member of the IL-17family, including IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F.IL-17-mediated diseases and conditions are characterized by highexpression of IL-17 and/or the accumulation or presence ofIL-17-positive cells in a tissue affected by the disease or condition.Similarly, IL-17-mediated diseases and conditions are diseases andconditions that are exacerbated by high IL-17 levels or an increase inIL-17 levels, and that are alleviated by low IL-17 levels or a reductionin IL-17 levels. The IL-17 inflammatory response may be local orsystemic.

Examples of diseases and conditions that may be mediated by IL-17 or theTh17 pathway include uveitis; cancer, such as breast cancer, lungcancer, liver cancer, colon cancer, or ovarian cancer; multiplesclerosis; arthritis, such as rheumatoid arthritis, osteoarthritis,psoriatic arthritis, or juvenile idiopathic arthritis; neuromyelitisoptica (Devic's disease); ankylosing spondylitis; spondyloarthritis;psoriasis; systemic lupus erythematosus; inflammatory bowel disease,such as Crohn's disease or ulcerative colitis; celiac disease; asthma,such as allergic asthma or neutrophilic asthma; chronic obstructivepulmonary disease (COPD); scleritis; vasculitis; Behcet's disease;atherosclerosis; atopic dermatitis; emphysema; periodontitis; allergicrhinitis; and allograft rejection. In preferred embodiments, thecompositions of the invention are used for treating or preventing one ormore of these conditions or diseases. In further preferred embodiments,these conditions or diseases are mediated by IL-17 or the Th17 pathway.In some embodiments, the disease or condition treated by the inventionis not colorectal cancer and/or colitis.

In some embodiments, the pathogenesis of the disease or conditionaffects the intestine. In some embodiments, the pathogenesis of thedisease or condition does not affect the intestine. In some embodiments,the pathogenesis of the disease or condition is not localized at theintestine. In some embodiments, the treating or preventing occurs at asite other than at the intestine. In some embodiments, the treating orpreventing occurs at the intestine and also at a site other than at theintestine. In certain embodiments, the disease or condition is systemic.

In certain embodiments, the compositions of the invention are for use ina method of reducing IL-17 production or reducing Th17 celldifferentiation in the treatment or prevention of a disease or conditionmediated by IL-17 or the Th17 pathway. In certain embodiments, thecompositions of the invention are for use in treating or preventing aninflammatory or autoimmune disease, wherein said treatment or preventionis achieved by reducing or preventing elevation of the Th17 inflammatoryresponse. In certain embodiments, the compositions of the invention arefor use in treating a subject with an inflammatory or autoimmunedisease, wherein the subject has elevated IL-17 levels or elevated Th17cells or is exhibiting a Th17 inflammatory response. In certainembodiments, the subject may have been diagnosed with a chronicinflammatory or autoimmune disease or condition, or the composition ofthe invention may be for use in preventing an inflammatory or autoimmunedisease or condition developing into a chronic inflammatory orautoimmune disease or condition. In certain embodiments, the disease orcondition may not be responsive to treatment with TNF-α inhibitors.These uses of the invention may be applied to any of the specificdisease or conditions listed in the preceding paragraph.

IL-17 and the Th17 pathway are often associated with chronicinflammatory and autoimmune diseases, so the compositions of theinvention may be particularly useful for treating or preventing chronicdiseases or conditions as listed above. In certain embodiments, thecompositions are for use in subjects with chronic disease. In certainembodiments, the compositions are for use in preventing the developmentof chronic disease.

The compositions of the invention may be useful for treating diseasesand conditions mediated by IL-17 or the Th17 pathway and for addressingthe Th17 inflammatory response, so the compositions of the invention maybe particularly useful for treating or preventing chronic disease,treating or preventing disease in subjects that have not responded toother therapies (such as treatment with TNF-α inhibitors), and/ortreating or preventing the tissue damage and symptoms associated withIL-17 and Th17 cells. For example, IL-17 is known to activate matrixdestruction in cartilage and bone tissue and IL-17 has an inhibitoryeffect on matrix production in chondrocytes and osteoblasts, so thecompositions of the invention may be useful for treating or preventingbone erosion or cartilage damage.

In certain embodiments, treatment with compositions of the inventionprovides a reduction or prevents an elevation in IL-17 levels, inparticular IL-17A levels. In certain embodiments, treatment withcompositions of the invention provides a reduction or prevents anelevation in TNFα, IFN-γ or IL-6 levels. Such reduction or prevention ofelevated levels of these cytokines may be useful for treating orpreventing inflammatory and autoimmune diseases and conditions, inparticular those mediated by IL-17 or the Th17 pathway.

Uveitis

In preferred embodiments, the compositions of the invention are for usein treating or preventing uveitis. The examples demonstrate that thecompositions of the invention achieve a reduction in disease incidenceand disease severity in an animal model of uveitis and so they may beuseful in the treatment or prevention of uveitis. Uveitis isinflammation of the uvea and can result in retinal tissue destruction.It can present in different anatomical forms (anterior, intermediate,posterior or diffuse) and result from different, but related, causes,including systemic autoimmune disorders. IL-17 and the Th17 pathway arecentrally involved in uveitis, so the efficacy of the compositions ofthe invention for treating uveitis indicates that the compositions ofthe invention may be particularly effective for treating and preventingdiseases and conditions mediated by IL-17 or the Th17 pathway.References [27-34] describe elevated serum levels of interleukin-17A insubjects with uveitis, specific association of IL17A genetic variantswith panuveitis, the role of Th17-associated cytokines in thepathogenesis of experimental autoimmune uveitis, the imbalance betweenTh17 Cells and regulatory T Cells during monophasic experimentalautoimmune uveitis, the up-regulation of IL-17A in subjects with uveitisand active Adamantiades-Behçet and Vogt-Koyanagi-Harada (VKH) diseases,the treatment of non-infectious uveitis with secukinumab (anti-IL-17Aantibody), and Th17 in uveitic eyes.

In certain embodiments, the uveitis is posterior uveitis. Posterioruveitis presents primarily with inflammation of the retina and choroidand the examples demonstrate that the compositions of the invention areeffective for reducing retinal inflammation and damage.

In certain embodiments, treatment with the compositions of the inventionresults in a reduction in retinal damage. In certain embodiments, thecompositions of the invention are for use in reducing or preventingretinal damage in the treatment of uveitis. In certain embodiments, thecompositions are for use in treating subjects with severe uveitis thatare at risk of retinal damage. In certain embodiments, treatment withthe compositions of the invention results in a reduction in optic discinflammation. In certain embodiments, the compositions of the inventionare for use in reducing or preventing optic disc inflammation. Incertain embodiments, treatment with the compositions of the inventionresults in a reduction in retinal tissue infiltration by inflammatorycells. In certain embodiments, the compositions of the invention are foruse in reducing retinal tissue infiltration by inflammatory cells. Incertain embodiments, treatment with the compositions of the inventionresults in vision being maintained or improved. In certain embodiments,the compositions of the invention are for use in maintaining orimproving vision.

In certain embodiments, the compositions are for use in treating orpreventing uveitis associated with a non-infectious or autoimmunedisease, such as Behçet disease, Crohn's disease, Fuchs heterochromiciridocyclitis, granulomatosis with polyangiitis, HLA-B27 relateduveitis, juvenile idiopathic arthritis, sarcoidosis, spondyloarthritis,sympathetic ophthalmia, tubulointerstitial nephritis and uveitissyndrome or Vogt-Koyanagi-Harada syndrome. IL-17A has been shown to beinvolved in, for example, Behçet and Vogt-Koyanagi-Harada diseases.

Treatment or prevention of uveitis may refer to, for example, analleviation of the severity of symptoms or a prevention of relapse.

Cancer

In preferred embodiments, the compositions of the invention are for usein treating or preventing cancer. IL-17 and the Th17 pathway havecentral roles in cancer development and progression, and so thecompositions of the invention may be useful for treating or preventingcancer.

Although the roles of IL-17 and Th17 cells in cancer are not fullyunderstood, numerous pro-tumor effects of IL-17 and Th17 cells areknown. For example, Th17 cells and IL-17 can promote angiogenesis,increase proliferation and survival of tumor cells and activatetumor-promoting transcription factors [35-37].

In certain embodiments, treatment with the compositions of the inventionresults in a reduction in tumor size or a reduction in tumor growth. Incertain embodiments, the compositions of the invention are for use inreducing tumor size or reducing tumor growth. The compositions of theinvention may be effective for reducing tumor size or growth. In certainembodiments, the compositions of the invention are for use in subjectswith solid tumors. In certain embodiments, the compositions of theinvention are for use in reducing or preventing angiogenesis in thetreatment of cancer. IL-17 and Th17 cells have central roles inangiogenesis. In certain embodiments, the compositions of the inventionare for use in preventing metastasis.

In certain embodiments, the compositions of the invention are for use intreating or preventing breast cancer. The compositions of the inventionmay be effective for treating breast cancer, and IL-17 and Th17 cellshave important roles in breast cancer [38]. In certain embodiments, thecompositions of the invention are for use in reducing tumor size,reducing tumor growth, or reducing angiogenesis in the treatment ofbreast cancer. In preferred embodiments the cancer is mammary carcinoma.In preferred embodiments the cancer is stage IV breast cancer.

In certain embodiments, the compositions of the invention are for use intreating or preventing lung cancer. The compositions of the inventionmay be effective for treating lung cancer, and IL-17 and Th17 cells haveimportant roles in lung cancer [39]. In certain embodiments, thecompositions of the invention are for use in reducing tumor size,reducing tumor growth, or reducing angiogenesis in the treatment of lungcancer. In preferred embodiments the cancer is lung carcinoma.

In certain embodiments, the compositions of the invention are for use intreating or preventing liver cancer. The compositions of the inventionmay be effective for treating liver cancer, and IL-17 and Th17 cellshave important roles in liver cancer [40]. In certain embodiments, thecompositions of the invention are for use in reducing tumor size,reducing tumor growth, or reducing angiogenesis in the treatment ofliver cancer. In preferred embodiments the cancer is hepatoma(hepatocellular carcinoma).

In certain embodiments, the compositions of the invention are for use intreating or preventing carcinoma. The compositions of the invention maybe particularly effective for treating carcinoma. In certainembodiments, the compositions of the invention are for use in treatingor preventing non-immunogenic cancer. The compositions of the inventionmay be effective for treating non-immunogenic cancers.

In further embodiments, the compositions of the invention are for use intreating or preventing acute lymphoblastic leukemia (ALL), acute myeloidleukemia, adrenocortical carcinoma, basal-cell carcinoma, bile ductcancer, bladder cancer, bone tumor, osteosarcoma/malignant fibroushistiocytoma, brainstem glioma, brain tumor, cerebellar astrocytoma,cerebral astrocytoma/malignant glioma, ependymoma, medulloblastoma,supratentorial primitive neuroectodermal tumors, breast cancer,bronchial adenomas/carcinoids, Burkitt's lymphoma, carcinoid tumor,cervical cancer, chronic lymphocytic leukemia, chronic myelogenousleukemia, chronic myeloproliferative disorders, colon cancer, cutaneousT-cell lymphoma, endometrial cancer, ependymoma, esophageal cancer,Ewing's sarcoma, intraocular melanoma, retinoblastoma, gallbladdercancer, gastric cancer, gastrointestinal carcinoid tumor,gastrointestinal stromal tumor (GIST), germ cell tumor, glioma,childhood visual pathway and hypothalamic, Hodgkin lymphoma, melanoma,islet cell carcinoma, Kaposi sarcoma, renal cell cancer, laryngealcancer, leukaemias, lymphomas, mesothelioma, neuroblastoma, non-Hodgkinlymphoma, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreaticcancer, parathyroid cancer, pharyngeal cancer, pituitary adenoma, plasmacell neoplasia, prostate cancer, renal cell carcinoma, retinoblastoma,sarcoma, testicular cancer, thyroid cancer, or uterine cancer.

The compositions of the invention may be particularly effective whenused in combination with further therapeutic agents. Theimmune-modulatory effects of the compositions of the invention may beeffective when combined with more direct anti-cancer agents. Therefore,in certain embodiments, the invention provides a composition comprisinga bacterial strain of the genus Eubacterium and an anticancer agent. Inpreferred embodiments the anticancer agent is an immune checkpointinhibitor, a targeted antibody immunotherapy, a CAR-T cell therapy, anoncolytic virus, or a cytostatic drug. In preferred embodiments, thecomposition comprises an anti-cancer agent selected from the groupconsisting of: Yervoy (ipilimumab, BMS); Keytruda (pembrolizumab,Merck); Opdivo (nivolumab, BMS); MEDI4736 (AZ/Medlmmune); MPDL3280A(Roche/Genentech); Tremelimumab (AZ/Medlmmune); CT-011 (pidilizumab,CureTech); BMS-986015 (lirilumab, BMS); MEDI0680 (AZ/Medlmmune);MSB-0010718C (Merck); PF-05082566 (Pfizer); MEDI6469 (AZ/Medlmmune);BMS-986016 (BMS); BMS-663513 (urelumab, BMS); IMP321 (Prima Biomed);LAG525 (Novartis); ARGX-110 (arGEN-X); PF-05082466 (Pfizer); CDX-1127(varlilumab; CellDex Therapeutics); TRX-518 (GITR Inc.); MK-4166(Merck); JTX-2011 (Jounce Therapeutics); ARGX-115 (arGEN-X); NLG-9189(indoximod, NewLink Genetics); INCB024360 (Incyte); IPH2201 (InnateImmotherapeutics/AZ); NLG-919 (NewLink Genetics); anti-VISTA (JnJ);Epacadostat (INCB24360, Incyte); F001287 (Flexus/BMS); CP 870893(University of Pennsylvania); MGA271 (Macrogenix); Emactuzumab(Roche/Genentech); Galunisertib (Eli Lilly); Ulocuplumab (BMS);BKT140/BL8040 (Biokine Therapeutics); Bavituximab (PeregrinePharmaceuticals); CC 90002 (Celgene); 852A (Pfizer); VTX-2337 (VentiRxPharmaceuticals); IMO-2055 (Hybridon, Idera Pharmaceuticals); LY2157299(Eli Lilly); EW-7197 (Ewha Women's University, Korea); Vemurafenib(Plexxikon); Dabrafenib (Genentech/GSK); BMS-777607 (BMS); BLZ945(Memorial Sloan-Kettering Cancer Centre); Unituxin (dinutuximab, UnitedTherapeutics Corporation); Blincyto (blinatumomab, Amgen); Cyramza(ramucirumab, Eli Lilly); Gazyva (obinutuzumab, Roche/Biogen); Kadcyla(ado-trastuzumab emtansine, Roche/Genentech); Perj eta (pertuzumab,Roche/Genentech); Adcetris (brentuximab vedotin, Takeda/Millennium);Arzerra (ofatumumab, GSK); Vectibix (panitumumab, Amgen); Avastin(bevacizumab, Roche/Genentech); Erbitux (cetuximab, BMS/Merck); Bexxar(tositumomab-1131, GSK); Zevalin (ibritumomab tiuxetan, Biogen); Campath(alemtuzumab, Bayer); Mylotarg (gemtuzumab ozogamicin, Pfizer);Herceptin (trastuzumab, Roche/Genentech); Rituxan (rituximab,Genentech/Biogen); volociximab (Abbvie); Enavatuzumab (Abbvie); ABT-414(Abbvie); Elotuzumab (Abbvie/BMS); ALX-0141 (Ablynx); Ozaralizumab(Ablynx); Actimab-C (Actinium); Actimab-P (Actinium); Milatuzumab-dox(Actinium); Emab-SN-38 (Actinium); Naptumonmab estafenatox (ActiveBiotech); AFM13 (Affimed); AFM11 (Affimed); AGS-16C3F (Agensys);AGS-16M8F (Agensys); AGS-22ME (Agensys); AGS-15ME (Agensys); GS-67E(Agensys); ALXN6000 (samalizumab, Alexion); ALT-836 (Altor Bioscience);ALT-801 (Altor Bioscience); ALT-803 (Altor Bioscience); AMG780 (Amgen);AMG 228 (Amgen); AMG820 (Amgen); AMG172 (Amgen); AMG595 (Amgen); AMG110(Amgen); AMG232 (adecatumumab, Amgen); AMG211 (Amgen/Medlmmune);BAY20-10112 (Amgen/Bayer); Rilotumumab (Amgen); Denosumab (Amgen);AMP-514 (Amgen); MEDI575 (AZ/Medlmmune); MEDI3617 (AZ/Medlmmune);MEDI6383 (AZ/Medlmmune); MEDI551 (AZ/Medlmmune); Moxetumomab pasudotox(AZ/Medlmmune); MEDI565 (AZ/Medlmmune); MEDI0639 (AZ/Medlmmune);MEDI0680 (AZ/Medlmmune); MEDI562 (AZ/Medlmmune); AV-380 (AVEO); AV203(AVEO); AV299 (AVEO); BAY79-4620 (Bayer); Anetumab ravtansine (Bayer);vantictumab (Bayer); BAY94-9343 (Bayer); Sibrotuzumab (BoehringerIngleheim); BI-836845 (Boehringer Ingleheim); B-701 (BioClin); BIIB015(Biogen); Obinutuzumab (Biogen/Genentech); BI-505 (Bioinvent); BI-1206(Bioinvent); TB-403 (Bioinvent); BT-062 (Biotest) BIL-010t (Biosceptre);MDX-1203 (BMS); MDX-1204 (BMS); Necitumumab (BMS); CAN-4 (Cantargia AB);CDX-011 (Celldex); CDX1401 (Celldex); CDX301 (Celldex); U3-1565 (DaiichiSankyo); patritumab (Daiichi Sankyo); tigatuzumab (Daiichi Sankyo);nimotuzumab (Daiichi Sankyo); DS-8895 (Daiichi Sankyo); DS-8873 (DaiichiSankyo); DS-5573 (Daiichi Sankyo); MORab-004 (Eisai); MORab-009 (Eisai);MORab-003 (Eisai); MORab-066 (Eisai); LY3012207 (Eli Lilly); LY2875358(Eli Lilly); LY2812176 (Eli Lilly); LY3012217 (Eli Lilly); LY2495655(Eli Lilly); LY3012212 (Eli Lilly); LY3012211 (Eli Lilly); LY3009806(Eli Lilly); cixutumumab (Eli Lilly); Flanvotumab (Eli Lilly); IMC-TR1(Eli Lilly); Ramucirumab (Eli Lilly); Tabalumab (Eli Lilly); Zanolimumab(Emergent Biosolution); FG-3019 (FibroGen); FPA008 (Five PrimeTherapeutics); FP-1039 (Five Prime Therapeutics); FPA144 (Five PrimeTherapeutics); catumaxomab (Fresenius Biotech); IMAB362 (Ganymed);IMAB027 (Ganymed); HuMax-CD74 (Genmab); HuMax-TFADC (Genmab); GS-5745(Gilead); GS-6624 (Gilead); OMP-21M18 (demcizumab, GSK); mapatumumab(GSK); IMGN289 (ImmunoGen); IMGN901 (ImmunoGen); IMGN853 (ImmunoGen);IMGN529 (ImmunoGen); IMMU-130 (Immunomedics); milatuzumab-dox(Immunomedics); IMMU-115 (Immunomedics); IMMU-132 (Immunomedics);IMMU-106 (Immunomedics); IMMU-102 (Immunomedics); Epratuzumab(Immunomedics); Clivatuzumab (Immunomedics); IPH41 (InnateImmunotherapeutics); Daratumumab (Janssen/Genmab); CNTO-95 (Intetumumab,Janssen); CNTO-328 (siltuximab, Janssen); KB004 (KaloBios);mogamulizumab (Kyowa Hakko Kirrin); KW-2871 (ecromeximab, Life Science);Sonepcizumab (Lpath); Margetuximab (Macrogenics); Enoblituzumab(Macrogenics); MGD006 (Macrogenics); MGF007 (Macrogenics); MK-0646(dalotuzumab, Merck); MK-3475 (Merck); Sym004 (Symphogen/Merck Serono);DI17E6 (Merck Serono); MOR208 (Morphosys); MOR202 (Morphosys); Xmab5574(Morphosys); BPC-1C (ensituximab, Precision Biologics); TAS266(Novartis); LFA102 (Novartis); BHQ880 (Novartis/Morphosys); QGE031(Novartis); HCD122 (lucatumumab, Novartis); LJM716 (Novartis); AT355(Novartis); OMP-21M18 (Demcizumab, OncoMed); OMP52M51 (Oncomed/GSK);OMP-59R5 (Oncomed/GSK); vantictumab (Oncomed/Bayer); CMC-544 (inotuzumabozogamicin, Pfizer); PF-03446962 (Pfizer); PF-04856884 (Pfizer);PSMA-ADC (Progenics); REGN1400 (Regeneron); REGN910 (nesvacumab,Regeneron/Sanofi); REGN421 (enoticumab, Regeneron/Sanofi); RG7221,RG7356, RG7155, RG7444, RG7116, RG7458, RG7598, RG7599, RG7600, RG7636,RG7450, RG7593, RG7596, DCDS3410A, RG7414 (parsatuzumab), RG7160(imgatuzumab), RG7159 (obintuzumab), RG7686, RG3638 (onartuzumab),RG7597 (Roche/Genentech); SAR307746 (Sanofi); SAR566658 (Sanofi);SAR650984 (Sanofi); SAR153192 (Sanofi); SAR3419 (Sanofi); SAR256212(Sanofi), SGN-LIV1A (lintuzumab, Seattle Genetics); SGN-CD33A (SeattleGenetics); SGN-75 (vorsetuzumab mafodotin, Seattle Genetics); SGN-19A(Seattle Genetics) SGN-CD70A (Seattle Genetics); SEA-CD40 (SeattleGenetics); ibritumomab tiuxetan (Spectrum); MLN0264 (Takeda); ganitumab(Takeda/Amgen); CEP-37250 (Teva); TB-403 (Thrombogenic); VB4-845(Viventia); Xmab2512 (Xencor); Xmab5574 (Xencor); nimotuzumab (YMBiosciences); Carlumab (Janssen); NY-ESO TCR (Adaptimmune); MAGE-A-10TCR (Adaptimmune); CTL019 (Novartis); JCAR015 (Juno Therapeutics);KTE-C19 CAR (Kite Pharma); UCART19 (Cellectis); BPX-401 (BellicumPharmaceuticals); BPX-601 (Bellicum Pharmaceuticals); ATTCK20 (UnumTherapeutics); CAR-NKG2D (Celyad); Onyx-015 (Onyx Pharmaceuticals); H101(Shanghai Sunwaybio); DNX-2401 (DNAtrix); VCN-01 (VCN Biosciences);Colo-Ad1 (PsiOxus Therapeutics); ProstAtak (Advantagene); Oncos-102(Oncos Therapeutics); CG0070 (Cold Genesys); Pexa-vac (JX-594, JennerexBiotherapeutics); GL-ONC1 (Genelux); T-VEC (Amgen); G207 (Medigene);HF10 (Takara Bio); SEPREHVIR (HSV1716, Virttu Biologics); OrienX010(OrienGene Biotechnology); Reolysin (Oncolytics Biotech); SVV-001(Neotropix); Cacatak (CVA21, Viralytics); Alimta (Eli Lilly), cisplatin,oxaliplatin, irinotecan, folinic acid, methotrexate, cyclophosphamide,5-fluorouracil, Zykadia (Novartis), Tafinlar (GSK), Xalkori (Pfizer),Iressa (AZ), Gilotrif (Boehringer Ingelheim), Tarceva (Astellas Pharma),Halaven (Eisai Pharma), Veliparib (Abbvie), AZD9291 (AZ), Alectinib(Chugai), LDK378 (Novartis), Genetespib (Synta Pharma),Tergenpumatucel-L (NewLink Genetics), GV1001 (Kael-GemVax), Tivantinib(ArQule); Cytoxan (BMS); Oncovin (Eli Lilly); Adriamycin (Pfizer);Gemzar (Eli Lilly); Xeloda (Roche); Ixempra (BMS); Abraxane (Celgene);Trelstar (Debiopharm); Taxotere (Sanofi); Nexavar (Bayer); IMMU-132(Immunomedics); E7449 (Eisai); Thermodox (Celsion); Cometriq (Exellxis);Lonsurf (Taiho Pharmaceuticals); Camptosar (Pfizer); UFT (TaihoPharmaceuticals); and TS-1 (Taiho Pharmaceuticals).

In some embodiments, the one or more Eubacterium bacterial strainsis/are the only therapeutically active agent(s) in a composition of theinvention. In some embodiments, the bacterial strain(s) in thecomposition is/are the only therapeutically active agent(s) in acomposition of the invention.

Asthma

In preferred embodiments, the compositions of the invention are for usein treating or preventing asthma. The compositions of the invention mayachieve a reduction in the recruitment of neutrophils and/or eosinophilsinto the airways following sensitization and challenge with house dustmite extract and so they may be useful in the treatment or prevention ofasthma. Asthma is a chronic disease characterized by inflammation andrestriction of the airways. The inflammation in asthma may be mediatedby IL-17 and/or Th17 cells, and so the compositions of the invention maybe particularly effective for preventing or treating asthma. Theinflammation in asthma may be mediated by eosinophils and/orneutrophils.

In certain embodiments, the asthma is eosinophilic or allergic asthma.Eosinophilic and allergic asthma are characterized by increased numbersof eosinophils in peripheral blood and in airway secretions and isassociated pathologically with thickening of the basement membrane zoneand pharmacologically by corticosteroid responsiveness [41].Compositions that reduce or inhibit eosinophil recruitment or activationmay be useful for treating or preventing eosinophilic and allergicasthma.

In additional embodiments, the compositions of the invention are for usein treating or preventing neutrophilic asthma (or non-eosinophilicasthma). High neutrophil numbers are associated with severe asthma thatmay be insensitive to corticosteroid treatment. Compositions that reduceor inhibit neutrophil recruitment or activation may be useful fortreating or preventing neutrophilic asthma.

Eosinophilic and neutrophilic asthma are not mutually exclusiveconditions and treatments that help address either the eosinophil andneutrophil responses may be useful for treating asthma in general.

Increased IL-17 levels and activation of the Th17 pathway are associatedwith severe asthma, so the compositions of the invention may be usefulfor preventing the development of severe asthma or for treating severeasthma.

In certain embodiments, the compositions of the invention are for use inmethods reducing an eosinophilic inflammatory response in the treatmentor prevention of asthma, or for use in methods of reducing aneutrophilic inflammatory response in the treatment or prevention ofasthma. As noted above, high levels of eosinophils in asthma isassociated pathologically with thickening of the basement membrane zone,so reducing eosinophilic inflammatory response in the treatment orprevention of asthma may be able to specifically address this feature ofthe disease. Also, elevated neutrophils, either in combination withelevated eosinophils or in their absence, is associated with severeasthma and chronic airway narrowing. Therefore, reducing theneutrophilic inflammatory response may be particularly useful foraddressing severe asthma.

In certain embodiments, the compositions reduce peribronchiolarinfiltration in allergic asthma, or are for use in reducingperibronchiolar infiltration in the treatment of allergic asthma. Incertain embodiments, the compositions reduce peribronchiolar and/orperivascular infiltration in neutrophilic asthma, or are for use inreducing peribronchiolar and/or perivascular infiltration in thetreatment of allergic neutrophilic asthma.

In certain embodiments, treatment with compositions of the inventionprovides a reduction or prevents an elevation in TNFα levels.

In certain embodiments, the compositions of the invention are for use ina method of treating asthma that results in a reduction of theeosinophilic and/or neutrophilic inflammatory response. In certainembodiments, the subject to be treated has, or has previously beenidentified as having, elevated neutrophil or eosinophil levels, forexample as identified through blood sampling or sputum analysis.

The compositions of the invention may be useful for preventing thedevelopment of asthma in a new-born when administered to the new-born,or to a pregnant woman. The compositions may be useful for preventingthe development of asthma in children. The compositions of the inventionmay be useful for treating or preventing adult-onset asthma. Thecompositions of the invention may be useful for managing or alleviatingasthma. The compositions of the invention may be particularly useful forreducing symptoms associated with asthma that is aggravated byallergens, such as house dust mites.

Treatment or prevention of asthma may refer to, for example, analleviation of the severity of symptoms or a reduction in the frequencyof exacerbations or the range of triggers that are a problem for thesubject.

Arthritis

In preferred embodiments, the compositions of the invention are for usein treating or preventing rheumatoid arthritis (RA). The compositions ofthe invention may achieve a reduction in the clinical signs of RA in amouse model, reduce cartilage and bone damage, and reduce the IL-17inflammatory response, and so they may be useful in the treatment orprevention of RA. RA is a systemic inflammatory disorder that primarilyaffects joints. RA is associated with an inflammatory response thatresults in swelling of joints, synovial hyperplasia, and destruction ofcartilage and bone. IL-17 and Th17 cells may have a key role in RA, forexample because IL-17 inhibits matrix production in chondrocytes andosteoblasts and activates the production and function of matrixmetalloproteinases and because RA disease activity is correlated toIL-17 levels and Th-17 cell numbers [42,43], so the compositions of theinvention may be particularly effective for preventing or treating RA.

In certain embodiments, the compositions of the invention are for use inlowering IL-17 levels or preventing elevation of IL-17 levels in thetreatment or prevention of RA. In certain embodiments, treatment withcompositions of the invention provides a reduction or prevents anelevation in IL-17 levels, in particular IL-17A levels. In certainembodiments, treatment with compositions of the invention provides areduction or prevents an elevation in IFN-γ or IL-6 levels.

In certain embodiments, treatment with the compositions of the inventionresults in a reduction in the swelling of joints. In certainembodiments, the compositions of the invention are for use in subjectswith swollen joints or subjects identified as at risk of having swollenjoints. In certain embodiments, the compositions of the invention arefor use in a method of reducing joint swelling in RA.

In certain embodiments, treatment with the compositions of the inventionresults in a reduction in cartilage damage or bone damage. In certainembodiments, the compositions of the invention are for use in reducingor preventing cartilage or bone damage in the treatment of RA. Incertain embodiments, the compositions are for use in treating subjectswith severe RA that are at risk of cartilage or bone damage.

Increased IL-17 levels and Th17 cell numbers are associated withcartilage and bone destruction in RA [42,43]. IL-17 is known to activatematrix destruction in cartilage and bone tissue and IL-17 has aninhibitory effect on matrix production in chondrocytes and osteoblasts.Therefore, in certain embodiments, the compositions of the invention arefor use in preventing bone erosion or cartilage damage in the treatmentof RA. In certain embodiments, the compositions are for use in treatingsubjects that exhibit bone erosion or cartilage damage or subjectsidentified as at risk of bone erosion or cartilage damage.

TNF-α is also associated with RA, but TNF-α is not involved in thepathogenesis of the later stages of the disease. In contrast, IL-17 hasa role throughout all stages of chronic disease [44]. Therefore, incertain embodiments the compositions of the invention are for use intreating chronic RA or late-stage RA, such as disease that includesjoint destruction and loss of cartilage. In certain embodiments, thecompositions of the invention are for treating subjects that havepreviously received anti-TNF-α therapy. In certain embodiments, thesubjects to be treated do not respond or no longer respond to anti-TNF-αtherapy.

The compositions of the invention may be useful for modulating asubject's immune system, so in certain embodiments the compositions ofthe invention are for use in preventing RA in a subject that has beenidentified as at risk of RA, or that has been diagnosed with early-stageRA. The compositions of the invention may be useful for preventing thedevelopment of RA.

The compositions of the invention may be useful for managing oralleviating RA. The compositions of the invention may be particularlyuseful for reducing symptoms associated with joint swelling or bonedestruction. Treatment or prevention of RA may refer to, for example, analleviation of the severity of symptoms or a reduction in the frequencyof exacerbations or the range of triggers that are a problem for thesubject.

Multiple Sclerosis

In preferred embodiments, the compositions of the invention are for usein treating or preventing multiple sclerosis. The compositions of theinvention may achieve a reduction in the disease incidence and diseaseseverity in a mouse model of multiple sclerosis (the EAE model), and sothey may be useful in the treatment or prevention of multiple sclerosis.Multiple sclerosis is an inflammatory disorder associated with damage tothe myelin sheaths of neurons, particularly in the brain and spinalcolumn. Multiple sclerosis is a chronic disease, which is progressivelyincapacitating and which evolves in episodes. IL-17 and Th17 cells mayhave a key role in multiple sclerosis, for example because IL-17 levelsmay correlate with multiple sclerosis lesions, IL-17 can disrupt bloodbrain barrier endothelial cell tight junctions, and Th17 cells canmigrate into the central nervous system and cause neuronal loss [45,46].Therefore, the compositions of the invention may be particularlyeffective for preventing or treating multiple sclerosis.

In certain embodiments, treatment with the compositions of the inventionresults in a reduction in disease incidence or disease severity. Incertain embodiments, the compositions of the invention are for use inreducing disease incidence or disease severity. In certain embodiments,treatment with the compositions of the invention prevents a decline inmotor function or results in improved motor function. In certainembodiments, the compositions of the invention are for use in preventinga decline in motor function or for use in improving motor function. Incertain embodiments, treatment with the compositions of the inventionprevents the development of paralysis. In certain embodiments, thecompositions of the invention are for use in preventing paralysis in thetreatment of multiple sclerosis.

The compositions of the invention may be useful for modulating asubject's immune system, so in certain embodiments the compositions ofthe invention are for use in preventing multiple sclerosis in a subjectthat has been identified as at risk of multiple sclerosis, or that hasbeen diagnosed with early-stage multiple sclerosis or“relapsing-remitting” multiple sclerosis. The compositions of theinvention may be useful for preventing the development of sclerosis.

The compositions of the invention may be useful for managing oralleviating multiple sclerosis. The compositions of the invention may beparticularly useful for reducing symptoms associated with multiplesclerosis. Treatment or prevention of multiple sclerosis may refer to,for example, an alleviation of the severity of symptoms or a reductionin the frequency of exacerbations or the range of triggers that are aproblem for the subject.

Modes of Administration

Preferably, the compositions of the invention are to be administered tothe gastrointestinal tract in order to enable delivery to and/or partialor total colonization of the intestine with the bacterial strain of theinvention. Generally, the compositions of the invention are administeredorally, but they may be administered rectally, intranasally, or viabuccal or sublingual routes.

In certain embodiments, the compositions of the invention may beadministered as a foam, as a spray or a gel.

In certain embodiments, the compositions of the invention may beadministered as a suppository, such as a rectal suppository, for examplein the form of a theobroma oil (cocoa butter), synthetic hard fat (e.g.suppocire, witepsol), glycero-gelatin, polyethylene glycol, or soapglycerin composition.

In certain embodiments, the composition of the invention is administeredto the gastrointestinal tract via a tube, such as a nasogastric tube,orogastric tube, gastric tube, jejunostomy tube (J tube), percutaneousendoscopic gastrostomy (PEG), or a port, such as a chest wall port thatprovides access to the stomach, jejunum and other suitable access ports.

The compositions of the invention may be administered once, or they maybe administered sequentially as part of a treatment regimen. In certainembodiments, the compositions of the invention are to be administereddaily.

In certain embodiments of the invention, treatment according to theinvention is accompanied by assessment of the subject's gut microbiota.Treatment may be repeated if delivery of and/or partial or totalcolonization with the strain of the invention is not achieved such thatefficacy is not observed, or treatment may be ceased if delivery and/orpartial or total colonization is successful and efficacy is observed.

In certain embodiments, the composition of the invention may beadministered to a pregnant animal, for example a mammal such as a humanin order to prevent an inflammatory or autoimmune disease developing inher child in utero and/or after it is born.

The compositions of the invention may be administered to a subject thathas been diagnosed with a disease or condition mediated by IL-17 or theTh17 pathway, or that has been identified as being at risk of a diseaseor condition mediated by IL-17 or the Th17 pathway. The compositions mayalso be administered as a prophylactic measure to prevent thedevelopment of diseases or conditions mediated by IL-17 or the Th17pathway in a healthy subject.

The compositions of the invention may be administered to a subject thathas been identified as having an abnormal gut microbiota. For example,the subject may have reduced or absent colonization by Eubacterium.

The compositions of the invention may be administered as a food product,such as a nutritional supplement.

Generally, the compositions of the invention are for the treatment ofhumans, although they may be used to treat animals including monogastricmammals such as poultry, pigs, cats, dogs, horses or rabbits. Thecompositions of the invention may be useful for enhancing the growth andperformance of animals. If administered to animals, oral gavage may beused.

Compositions

Generally, the composition of the invention comprises bacteria. Inpreferred embodiments of the invention, the composition is formulated infreeze-dried form. For example, the composition of the invention maycomprise granules or gelatin capsules, for example hard gelatincapsules, comprising a bacterial strain of the invention.

Preferably, the composition of the invention comprises lyophilizedbacteria.

Lyophilization of bacteria is a well-established procedure and relevantguidance is available in, for example, references [47-49].

Alternatively, the composition of the invention may comprise a live,active bacterial culture.

In some embodiments, the bacterial strain in the composition of theinvention has not been inactivated, for example, has not beenheat-inactivated. In some embodiments, the bacterial strain in thecomposition of the invention has not been killed, for example, has notbeen heat-killed. In some embodiments, the bacterial strain in thecomposition of the invention has not been attenuated, for example, hasnot been heat-attenuated. For example, in some embodiments, thebacterial strain in the composition of the invention has not beenkilled, inactivated and/or attenuated. For example, in some embodiments,the bacterial strain in the composition of the invention is live. Forexample, in some embodiments, the bacterial strain in the composition ofthe invention is viable. For example, in some embodiments, the bacterialstrain in the composition of the invention is capable of at leastpartially or totally colonizing the intestine. For example, in someembodiments, the bacterial strain in the composition of the invention isviable and capable of at least partially or totally colonizing theintestine.

In some embodiments, the composition comprises a mixture of livebacterial strains and bacterial strains that have been killed.

In preferred embodiments, the composition of the invention isencapsulated to enable delivery of the bacterial strain to theintestine. Encapsulation protects the composition from degradation untildelivery at the target location through, for example, rupturing withchemical or physical stimuli such as pressure, enzymatic activity, orphysical disintegration, which may be triggered by changes in pH. Anyappropriate encapsulation method may be used. Exemplary encapsulationtechniques include entrapment within a porous matrix, attachment oradsorption on solid carrier surfaces, self-aggregation by flocculationor with cross-linking agents, and mechanical containment behind amicroporous membrane or a microcapsule. Guidance on encapsulation thatmay be useful for preparing compositions of the invention is availablein, for example, references [50] and [51].

The composition may be administered orally and may be in the form of atablet, capsule or powder. Encapsulated products are preferred becauseEubacterium contortum are anaerobes. Other ingredients (such as vitaminC, for example), may be included as oxygen scavengers and prebioticsubstrates to improve the delivery and/or partial or total colonizationand survival in vivo. Alternatively, the probiotic composition of theinvention may be administered orally as a food or nutritional product,such as milk or whey based fermented dairy product, or as apharmaceutical product.

The composition may be formulated as a probiotic.

A composition of the invention includes a therapeutically effectiveamount of a bacterial strain of the invention. A therapeuticallyeffective amount of a bacterial strain is sufficient to exert abeneficial effect upon a subject. A therapeutically effective amount ofa bacterial strain may be sufficient to result in delivery to and/orpartial or total colonization of the subject's intestine.

A suitable daily dose of the bacteria, for example for an adult human,may be from about 1×10³ to about 1×10¹¹ colony forming units (CFU); forexample, from about 1×10⁷ to about 1×10¹⁰ CFU; in another example fromabout 1×10⁶ to about 1×10¹⁰ CFU.

In certain embodiments, the composition contains the bacterial strain inan amount of from about 1×10⁶ to about 1×10¹¹ CFU/g, respect to theweight of the composition; for example, from about 1×10⁸ to about 1×10¹⁰CFU/g. The dose may be, for example, 1 g, 3 g, 5 g, and 10 g.

Typically, a probiotic, such as the composition of the invention, isoptionally combined with at least one suitable prebiotic compound. Aprebiotic compound is usually a non-digestible carbohydrate such as anoligo- or polysaccharide, or a sugar alcohol, which is not degraded orabsorbed in the upper digestive tract. Known prebiotics includecommercial products such as inulin and transgalacto-oligosaccharides.

In certain embodiments, the probiotic composition of the presentinvention includes a prebiotic compound in an amount of from about 1 toabout 30% by weight, respect to the total weight composition, (e.g. from5 to 20% by weight). Carbohydrates may be selected from the groupconsisting of: fructo-oligosaccharides (or FOS), short-chainfructo-oligosaccharides, inulin, isomalt-oligosaccharides, pectins,xylo-oligosaccharides (or XOS), chitosan-oligosaccharides (or COS),beta-glucans, arable gum modified and resistant starches, polydextrose,D-tagatose, acacia fibers, carob, oats, and citrus fibers. In oneaspect, the prebiotics are the short-chain fructo-oligosaccharides (forsimplicity shown herein below as FOSs-c.c); said FOSs-c.c. are notdigestible carbohydrates, generally obtained by the conversion of thebeet sugar and including a saccharose molecule to which three glucosemolecules are bonded.

The compositions of the invention may comprise pharmaceuticallyacceptable excipients or carriers. Examples of such suitable excipientsmay be found in the reference [52]. Acceptable carriers or diluents fortherapeutic use are well known in the pharmaceutical art and aredescribed, for example, in reference [53]. Examples of suitable carriersinclude lactose, starch, glucose, methyl cellulose, magnesium stearate,mannitol, sorbitol and the like. Examples of suitable diluents includeethanol, glycerol and water. The choice of pharmaceutical carrier,excipient or diluent can be selected with regard to the intended routeof administration and standard pharmaceutical practice. Thepharmaceutical compositions may comprise as, or in addition to, thecarrier, excipient or diluent any suitable binder(s), lubricant(s),suspending agent(s), coating agent(s), solubilizing agent(s). Examplesof suitable binders include starch, gelatin, natural sugars such asglucose, anhydrous lactose, free-flow lactose, beta-lactose, cornsweeteners, natural and synthetic gums, such as acacia, tragacanth orsodium alginate, carboxymethyl cellulose and polyethylene glycol.Examples of suitable lubricants include sodium oleate, sodium stearate,magnesium stearate, sodium benzoate, sodium acetate, sodium chloride andthe like. Preservatives, stabilizers, dyes and even flavoring agents maybe provided in the pharmaceutical composition. Examples of preservativesinclude sodium benzoate, sorbic acid and esters of p-hydroxybenzoicacid. Antioxidants and suspending agents may be also used.

The compositions of the invention may be formulated as a food product.For example, a food product may provide nutritional benefit in additionto the therapeutic effect of the invention, such as in a nutritionalsupplement. Similarly, a food product may be formulated to enhance thetaste of the composition of the invention or to make the compositionmore attractive to consume by being more similar to a common food item,rather than to a pharmaceutical composition. In certain embodiments, thecomposition of the invention is formulated with a nutritious productsuch as a milk-based product. The term “milk-based product” means anyliquid or semi-solid milk- or whey-based product having a varying fatcontent. The milk-based product can be, e.g., cow's milk, goat's milk,sheep's milk, skimmed milk, whole milk, milk recombined from powderedmilk and whey without any processing, or a processed product, such asyoghurt, curdled milk, curd, sour milk, sour whole milk, butter milk andother sour milk products. Another important group includes milkbeverages, such as whey beverages, fermented milks, condensed milks,infant or baby milks; flavored milks, ice cream; milk-containing foodsuch as sweets.

In some embodiments, the compositions of the invention comprise one ormore bacterial strains of the genus Eubacterium and do not containbacteria from any other genus, or which comprise only de minimis orbiologically irrelevant amounts of bacteria from another genus. Thus, insome embodiments, the invention provides a composition comprising one ormore bacterial strains of the genus Eubacterium, which does not containbacteria from any other genus or which comprises only de minimis orbiologically irrelevant amounts of bacteria from another genus, for usein therapy.

In certain embodiments, the compositions of the invention contain asingle bacterial strain or species and do not contain any otherbacterial strains or species. Such compositions may comprise only deminimis or biologically irrelevant amounts of other bacterial strains orspecies. Such compositions may be a culture that is substantially freefrom other species of organism. Thus, in some embodiments, the inventionprovides a composition comprising a single bacterial strain or speciesof the genus Eubacterium, which does not contain bacteria from any othergenus or which comprises only de minimis or biologically irrelevantamounts of bacteria from another genus for use in therapy. In someembodiments, the composition consists essentially of a bacteria strainof genus Eubacterium.

In some embodiments, the compositions of the invention comprise morethan one bacterial strain or species. For example, in some embodiments,the compositions of the invention comprise more than one strain fromwithin the same species (e.g. more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,15, 20, 25, 30, 35, 40 or 45 strains), and, optionally, do not containbacteria from any other species. In some embodiments, the compositionsof the invention comprise less than 50 strains from within the samespecies (e.g. less than 45, 40, 35, 30, 25, 20, 15, 12, 10, 9, 8, 7, 6,5, 4 or 3 strains), and, optionally, do not contain bacteria from anyother species. In some embodiments, the compositions of the inventioncomprise 1-40, 1-30, 1-20, 1-19, 1-18, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6,1-5, 1-4, 1-3, 1-2, 2-50, 2-40, 2-30, 2-20, 2-15, 2-10, 2-5, 6-30, 6-15,16-25, or 31-50 strains from within the same species and, optionally, donot contain bacteria from any other species. In some embodiments, thecompositions of the invention comprise more than one species from withinthe same genus (e.g. more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15,17, 20, 23, 25, 30, 35 or 40 species), and, optionally, do not containbacteria from any other genus. In some embodiments, the compositions ofthe invention comprise less than 50 species from within the same genus(e.g. less than 50, 45, 40, 35, 30, 25, 20, 15, 12, 10, 8, 7, 6, 5, 4 or3 species), and, optionally, do not contain bacteria from any othergenus. In some embodiments, the compositions of the invention comprise1-50, 1-40, 1-30, 1-20, 1-15, 1-10, 1-9, 1-8, 1-7, 1-6, 1-5, 1-4, 1-3,1-2, 2-50, 2-40, 2-30, 2-20, 2-15, 2-10, 2-5, 6-30, 6-15, 16-25, or31-50 species from within the same genus and, optionally, do not containbacteria from any other genus. The invention comprises any combinationof the foregoing. In some embodiments, the composition comprises amicrobial consortium. For example, in some embodiments, the compositioncomprises the Eubacterium bacterial strain as part of a microbialconsortium. For example, in some embodiments, the Eubacterium bacterialstrain is present in combination with one or more (e.g. at least 2, 3,4, 5, 10, 15 or 20) other bacterial strains from other genera with whichit can live symbiotically in vivo in the intestine. For example, in someembodiments, the composition comprises a bacterial strain of Eubacteriumcontortum in combination with a bacterial strain from a different genus.In some embodiments, the microbial consortium comprises two or morebacterial strains obtained from a faeces sample of a single organism,e.g. a human. In some embodiments, the microbial consortium is not foundtogether in nature. For example, in some embodiments, the microbialconsortium comprises bacterial strains obtained from faeces samples ofat least two different organisms. In some embodiments, the two differentorganisms are from the same species, e.g. two different humans. In someembodiments, the two different organisms are an infant human and anadult human. In some embodiments, the two different organisms are twodifferent adult humans. In some embodiments, the two different organismsare a human and a non-human mammal.

In some embodiments, the composition of the invention additionallycomprises a bacterial strain that has the same safety and therapeuticefficacy characteristics as strain MRX050 deposited as NCIMB 42689, butwhich is not MRX050 deposited as NCIMB 42689, or which is not aEubacterium contortum, or which is not a Eubacterium.

In some embodiments in which the composition of the invention comprisesmore than one bacterial strain, species or genera, the individualbacterial strains, species or genera may be for separate, simultaneousor sequential administration. For example, the composition may compriseall of the more than one bacterial strain, species or genera, or thebacterial strains, species or genera may be stored separately and beadministered separately, simultaneously or sequentially. In someembodiments, the more than one bacterial strains, species or genera arestored separately but are mixed together prior to use.

In some embodiments, the bacterial strain for use in the invention isobtained from human adult faeces. In some embodiments in which thecomposition of the invention comprises more than one bacterial strain,all of the bacterial strains are obtained from human adult faeces or ifother bacterial strains are present they are present only in de minimisamounts. The bacteria may have been cultured subsequent to beingobtained from the human adult faeces and being used in a composition ofthe invention.

As mentioned above, in some embodiments, the bacterial strain of theinvention is the only therapeutically active agent in a composition ofthe invention. In some embodiments, the bacterial strain(s) in thecomposition is/are the only therapeutically active agent(s) in acomposition of the invention.

The compositions for use in accordance with the invention may or may notrequire marketing approval.

In certain embodiments, the invention provides the above pharmaceuticalcomposition, wherein said bacterial strain is lyophilized. In certainembodiments, the invention provides the above pharmaceuticalcomposition, wherein said bacterial strain is spray dried. In certainembodiments, the invention provides the above pharmaceuticalcomposition, wherein the bacterial strain is lyophilized or spray driedand wherein it is live. In certain embodiments, the invention providesthe above pharmaceutical composition, wherein the bacterial strain islyophilized or spray dried and wherein it is viable. In certainembodiments, the invention provides the above pharmaceuticalcomposition, wherein the bacterial strain is lyophilized or spray driedand wherein it is capable of at least partially or totally colonizingthe intestine. In certain embodiments, the invention provides the abovepharmaceutical composition, wherein the bacterial strain is lyophilizedor spray dried and wherein it is viable and capable of at leastpartially or totally colonizing the intestine.

In some cases, the lyophilized or spray dried bacterial strain isreconstituted prior to administration. In some cases, the reconstitutionis by use of a diluent described herein.

The compositions of the invention can comprise pharmaceuticallyacceptable excipients, diluents or carriers.

In certain embodiments, the invention provides a pharmaceuticalcomposition comprising: a bacterial strain as used in the invention; anda pharmaceutically acceptable excipient, carrier or diluent; wherein thebacterial strain is in an amount sufficient to treat a disorder whenadministered to a subject in need thereof; and wherein the disorder isselected from the group consisting of uveitis; cancer, such as breastcancer, lung cancer, liver cancer, colon cancer, or ovarian cancer;multiple sclerosis; arthritis, such as rheumatoid arthritis,osteoarthritis, psoriatic arthritis, or juvenile idiopathic arthritis;neuromyelitis optica (Devic's disease); ankylosing spondylitis;spondyloarthritis; psoriasis; systemic lupus erythematosus; inflammatorybowel disease, such as Crohn's disease or ulcerative colitis; celiacdisease; asthma, such as allergic asthma or neutrophilic asthma; chronicobstructive pulmonary disease (COPD); scleritis; vasculitis; Behcet'sdisease; atherosclerosis; atopic dermatitis; emphysema; periodontitis;allergic rhinitis; and allograft rejection.

In certain embodiments, the invention provides pharmaceuticalcomposition comprising: a bacterial strain as used in the invention; anda pharmaceutically acceptable excipient, carrier or diluent; wherein thebacterial strain is in an amount sufficient to treat or prevent adisease or condition mediated by IL-17 or the Th17 pathway. In preferredembodiments, said disease or condition is selected from the groupconsisting of uveitis; cancer, such as breast cancer, lung cancer, livercancer, colon cancer, or ovarian cancer; multiple sclerosis; arthritis,such as rheumatoid arthritis, osteoarthritis, psoriatic arthritis, orjuvenile idiopathic arthritis; neuromyelitis optica (Devic's disease);ankylosing spondylitis; spondyloarthritis; psoriasis; systemic lupuserythematosus; inflammatory bowel disease, such as Crohn's disease orulcerative colitis; celiac disease; asthma, such as allergic asthma orneutrophilic asthma; chronic obstructive pulmonary disease (COPD);scleritis; vasculitis; Behcet's disease; atherosclerosis; atopicdermatitis; emphysema; periodontitis; allergic rhinitis; and allograftrejection.

In certain embodiments, the invention provides the above pharmaceuticalcomposition, wherein the amount of the bacterial strain is from about1×10³ to about 1×10¹¹ colony forming units per gram with respect to aweight of the composition.

In certain embodiments, the invention provides the above pharmaceuticalcomposition, wherein the composition is administered at a dose of 1 g, 3g, 5 g or 10 g of the composition.

In certain embodiments, the invention provides the above pharmaceuticalcomposition, wherein the composition is administered by a methodselected from the group consisting of oral, rectal, subcutaneous, nasal,buccal, and sublingual.

In certain embodiments, the invention provides the above pharmaceuticalcomposition, comprising a carrier selected from the group consisting oflactose, starch, glucose, methyl cellulose, magnesium stearate, mannitoland sorbitol.

In certain embodiments, the invention provides the above pharmaceuticalcomposition, comprising a diluent selected from the group consisting ofethanol, glycerol and water.

In certain embodiments, the invention provides the above pharmaceuticalcomposition, comprising an excipient selected from the group consistingof starch, gelatin, glucose, anhydrous lactose, free-flow lactose,beta-lactose, corn sweetener, acacia, tragacanth, sodium alginate,carboxymethyl cellulose, polyethylene glycol, sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate and sodiumchloride.

In certain embodiments, the invention provides the above pharmaceuticalcomposition, further comprising at least one of a preservative, anantioxidant and a stabilizer.

In certain embodiments, the invention provides the above pharmaceuticalcomposition, comprising a preservative selected from the groupconsisting of sodium benzoate, sorbic acid and esters ofp-hydroxybenzoic acid.

In certain embodiments, the invention provides the above pharmaceuticalcomposition, wherein when the composition is stored in a sealedcontainer at about 4.0 or about 25.0 and the container is placed in anatmosphere having 50% relative humidity, at least 80% of the bacterialstrain as measured in colony forming units, remains after a period of atleast about: 1 month, 3 months, 6 months, 1 year, 1.5 years, 2 years,2.5 years or 3 years.

In some embodiments, the composition of the invention is provided in asealed container comprising a composition as described herein. In someembodiments, the sealed container is a sachet or bottle. In someembodiments, the composition of the invention is provided in a syringecomprising a composition as described herein.

The composition of the present invention may, in some embodiments, beprovided as a pharmaceutical formulation. For example, the compositionmay be provided as a tablet or capsule. In some embodiments, the capsuleis a gelatine capsule (“gel-cap”).

In some embodiments, the compositions of the invention are administeredorally. Oral administration may involve swallowing, so that the compoundenters the gastrointestinal tract, and/or buccal, lingual, or sublingualadministration by which the compound enters the blood stream directlyfrom the mouth.

Pharmaceutical formulations suitable for oral administration includesolid plugs, solid microparticulates, semi-solid and liquid (includingmultiple phases or dispersed systems) such as tablets; soft or hardcapsules containing multi- or nano-particulates, liquids (e.g. aqueoussolutions), emulsions or powders; lozenges (including liquid-filled);chews; gels; fast dispersing dosage forms; films; ovules; sprays; andbuccal/mucoadhesive patches.

In some embodiments the pharmaceutical formulation is an entericformulation, i.e. a gastro-resistant formulation (for example, resistantto gastric pH) that is suitable for delivery of the composition of theinvention to the intestine by oral administration. Enteric formulationsmay be particularly useful when the bacteria or another component of thecomposition is acid-sensitive, e.g. prone to degradation under gastricconditions.

In some embodiments, the enteric formulation comprises an entericcoating. In some embodiments, the formulation is an enteric-coateddosage form. For example, the formulation may be an enteric-coatedtablet or an enteric-coated capsule, or the like. The enteric coatingmay be a conventional enteric coating, for example, a conventionalcoating for a tablet, capsule, or the like for oral delivery. Theformulation may comprise a film coating, for example, a thin film layerof an enteric polymer, e.g. an acid-insoluble polymer.

In some embodiments, the enteric formulation is intrinsically enteric,for example, gastro-resistant without the need for an enteric coating.Thus, in some embodiments, the formulation is an enteric formulationthat does not comprise an enteric coating. In some embodiments, theformulation is a capsule made from a thermogelling material. In someembodiments, the thermogelling material is a cellulosic material, suchas methylcellulose, hydroxymethylcellulose orhydroxypropylmethylcellulose (HPMC). In some embodiments, the capsulecomprises a shell that does not contain any film forming polymer. Insome embodiments, the capsule comprises a shell and the shell compriseshydroxypropylmethylcellulose and does not comprise any film formingpolymer (e.g. see [54]). In some embodiments, the formulation is anintrinsically enteric capsule (for example, Vcaps® from Capsugel).

In some embodiments, the formulation is a soft capsule. Soft capsulesare capsules which may, owing to additions of softeners, such as, forexample, glycerol, sorbitol, maltitol and polyethylene glycols, presentin the capsule shell, have a certain elasticity and softness. Softcapsules can be produced, for example, on the basis of gelatine orstarch. Gelatine-based soft capsules are commercially available fromvarious suppliers. Depending on the method of administration, such as,for example, orally or rectally, soft capsules can have various shapes,they can be, for example, round, oval, oblong or torpedo-shaped. Softcapsules can be produced by conventional processes, such as, forexample, by the Scherer process, the Accogel process or the droplet orblowing process.

Culturing Methods

The bacterial strains for use in the present invention can be culturedusing standard microbiology techniques as detailed in, for example,references [55-57].

The solid or liquid medium used for culture may be YCFA agar or YCFAmedium. YCFA medium may include (per 100 ml, approximate values):Casitone (1.0 g), yeast extract (0.25 g), NaHCO₃ (0.4 g), cysteine (0.1g), K₂HPO₄ (0.045 g), KH₂PO₄ (0.045 g), NaCl (0.09 g), (NH₄)₂SO₄ (0.09g), MgSO₄.7H₂O (0.009 g), CaCl₂ (0.009 g), resazurin (0.1 mg), hemin (1mg), biotin (1 μg), cobalamin (1 μg), p-aminobenzoic acid (3 μg), folicacid (5 μg), and pyridoxamine (15 μg).

Bacterial Strains for Use in Vaccine Compositions

The inventors have identified that the bacterial strains of theinvention are useful for treating or preventing diseases or conditionsmediated by IL-17 or the Th17 pathway. This is likely to be a result ofthe effect that the bacterial strains of the invention have on the hostimmune system. Therefore, the compositions of the invention may also beuseful for preventing diseases or conditions mediated by IL-17 or theTh17 pathway, when administered as vaccine compositions. In certain suchembodiments, the bacterial strains of the invention are viable. Incertain such embodiments, the bacterial strains of the invention arecapable of at least partially or totally colonizing the intestine. Incertain such embodiments, the bacterial strains of the invention areviable and capable of at least partially or totally colonizing theintestine. In other certain such embodiments, the bacterial strains ofthe invention may be killed, inactivated or attenuated. In certain suchembodiments, the compositions may comprise a vaccine adjuvant. Incertain embodiments, the compositions are for administration viainjection, such as via subcutaneous injection.

General

The practice of the present invention will employ, unless otherwiseindicated, conventional methods of chemistry, biochemistry, molecularbiology, immunology and pharmacology, within the skill of the art. Suchtechniques are explained fully in the literature. See, e.g., references[58] and [59-65], etc.

A subject treated by a method described herein, or by contact with oradministration of a composition described herein can be a mammaliansubject who can be a human subject, a non-human primate, a caninemammal, a felid mammal or any other mammal. A subject maybe a patientwho is a mammalian patient for instance, a human patient, a non-humanprimate, a canine mammal, a felid mammal or any other mammalian patient.

The term “comprising” encompasses “including” as well as “consisting”e.g. a composition “comprising” X may consist exclusively of X or mayinclude something additional e.g. X+Y.

The term “about” in relation to a numerical value x is optional andmeans, for example, x+10%.

The word “substantially” does not exclude “completely” e.g. acomposition which is “substantially free” from Y may be completely freefrom Y. Where necessary, the word “substantially” may be omitted fromthe definition of the invention.

References to a percentage sequence identity between two nucleotidesequences means that, when aligned, that percentage of nucleotides arethe same in comparing the two sequences. This alignment and the percenthomology or sequence identity can be determined using software programsknown in the art, for example those described in section 7.7.18 of ref[66]. A preferred alignment is determined by the Smith-Waterman homologysearch algorithm using an affine gap search with a gap open penalty of12 and a gap extension penalty of 2, BLOSUM matrix of 62. TheSmith-Waterman homology search algorithm is disclosed in ref [67].

Unless specifically stated, a process or method comprising numeroussteps may comprise additional steps at the beginning or end of themethod, or may comprise additional intervening steps. Also, steps may becombined, omitted or performed in an alternative order, if appropriate.

Various embodiments of the invention are described herein. It will beappreciated that the features specified in each embodiment may becombined with other specified features, to provide further embodiments.In particular, embodiments highlighted herein as being suitable, typicalor preferred may be combined with each other (except when they aremutually exclusive).

MODES FOR CARRYING OUT THE INVENTION Example 1—Efficacy of BacterialInocula in a Mouse Model of Uveitis Summary

This study used a mouse model of interphotoreceptor retinoid-bindingprotein (IRBP)-induced uveitis to test the effects of bacterialadministration on uveitis. Uveitis is a sight-threatening conditionresulting from intraocular inflammation and retinal tissue destruction.This disease can be studied in rodents in a model of experimentalautoimmune uveoretinitis (EAU) [68]. EAU is an organ-specific disorderwhere Th1/Th17 cells are directed toward retinal antigens and producecytokines that activate resident and infiltrating mononuclear cellsleading to tissue destruction. EAU can be induced in mice by challengewith retinal antigens including interphotoreceptor retinoid bindingprotein peptide (IRBPp). Disease onset normally occurs from day 8-9 andpeaks after days 14-15. Signs of clinical disease can be monitored usingtopical endoscopic fundal imaging (TEFI).

Strain

MRX050: Eubacterium contortum.

The strain used in this example has been deposited as NCIMB 42689.

Biotherapeutic was provided in glycerol stock. Microbiological growthmedia (YCFA) was used for the culture of the agent.

Mice

The mice were strain C57BL/6 and were over 6 weeks old at the beginningof the study. 72 mice were used (+36 Satellite animals). Unhealthyanimals were excluded from the study. Animals were housed in specificpathogen free (spf) conditions, in a thermostatically monitored holdingroom (22±4° C.). Animals were allowed to acclimatize under standardanimal house conditions for a minimum of one week prior to use. Thehealth status of the animals was monitored throughout this period andthe suitability of each animal for experimental use was assessed priorto study start. Mice were housed in groups of up to 10 animals per cagefor the duration of the study. Irradiated pellet diet (Lab diet, EURodent diet 22%, 5LF5) and water were available ad libitum throughoutthe acclimatization and study periods. It is unlikely that anyconstituent of the diet or water interfered with the study.

Experimental Outline

Adult female C57BL/6 mice were randomly allocated to experimental groupsand allowed to acclimatize for one week. Treatments were administeredaccording to the schedule below. On Day 0, animals were administeredwith an emulsion containing 200 μg of interphotoreceptor retinoidbinding protein peptide 1-20 (IRBP p1-20) in complete Freund's adjuvant(CFA) supplemented with 2.5 mg/ml Mycobacterium Tuberculosis H37 Ra bysubcutaneous injection. Also on Day 0, animals were administered with1.5 μg Bordetella Pertussis toxin by intra-peritoneal injection. FromDay −14, animals are weighed three times per week. From Day −1 until theend of the experiment on Day 42, animals are monitored twice per weekfor clinical signs of uveitis using topical endoscopic fundal imaging(TEFI).

Administration Schedule

-   -   All Groups are n=12    -   Vehicle for oral administration is YCFA medium.    -   Administration volume for twice daily oral administration is 5        ml/kg.

Group Treatment Dose Route Frequency Disease Induction 1 Vehicle 5 ml/kgPO BID Day 0: IRBP/CFA, Day-14-End SC 2 MRX050 5 ml/kg Day 0: PTx, IPPO: oral administration, BID: twice daily, SC: subcutaneous injection,IP: intra-peritoneal injection, IRBP: interphotoreceptor bindingprotein, CFA: complete Freund's adjuvant, PTx: Pertussis toxin

A positive control group was also tested using treatment with the drugcyclosporin A.

Readouts

Bodyweights.

From Day −14, animals are weighed three times a week. Animals with abodyweight loss equal to or greater than 15% of their initial (Day 0)bodyweight on two consecutive occasions are culled.

Non-Specific Clinical Observations.

From Day −14 until the end of the experiment, animals are checked dailyfor non-specific clinical signs to include abnormal posture (hunched),abnormal coat condition (piloerection) and abnormal activity levels(reduced or increased activity).

Clinical Scores: Retinal Imaging by Topical Endoscopic Fundal Imaging(TEFI).

From Day −1 until the end of the experiment, animals are scored twiceper week for clinical signs of uveitis. Retinal images are capturedusing TEFI in non-anaesthetized but restrained animals following pupildilatation using Tropicamide 1% then Phenylephrine hydrochloride 2.5%.Retinal images are scores using the following system. The maximumcumulative score is 20.

Optic disc Retinal tissue Score Inflammation Retinal vesselsInfiltration Structural damage 1 Minimal 1-4 mild cuffings 1-4 smalllesions or Retinal lesions or 1 linear lesion atrophy involving ¼ to ¾of retinal area 2 Mild >4 mild cuffings or 5-10 small lesions Panretinalatrophy 1-3 moderate or 2-3 linear lesions with multiple small cuffingslesions (scars) or ≤3 linear lesions (scars) 3 Moderate >3 moderate >10small lesions or Panretinal atrophy cuffings >3 linear lesions with >3linear lesions or confluent lesions (scars) 4 Severe >1 severe cuffingsLinear lesion Retinal detachment confluent with folding 5 Not visible(white-out or severe detachment)

Results

The results of the study are shown in FIGS. 1 and 2.

Clinical Scores: Retinal Imaging by Topical Endoscopic Fundal Imaging(TEFI).

TEFI scores data measured in the Control group from Day 0 until Day 28were analyzed by Kruskal-Wallis test for non-parametric data followed byDunn's post-test for multiple comparisons between experimental days.

IRBP administration induced a significant increase in the TEFI scoresmeasured from Day 14 (p<0.01) and on Day 28 (p<0.0001) when compared toDay 0 in the Control group (FIG. 1).

TEFI scores measured in the experimental groups on Day 28 were analyzedusing a one-way ANOVA. As expected, a significant decrease in the scoreswas observed in the positive control cyclosporine A group. There wasalso a statistically significant decrease in the scores for theMRX050-treated group (p<0.001), relative to the negative control (FIG.2).

Conclusions.

Clinical scores determined by TEFI increased from Day 14, as expected inthis model of IRBP-induced uveitis. By Day 28, a striking andstatistically significant reduction in disease incidence and diseaseseverity was observed in the MRX050-treated group, which was comparableto that seen for the positive control group. In particular, these dataindicate that treatment with the strain MRX050 reduced retinal damage,optic disc inflammation and/or retinal tissue infiltration byinflammatory cells (see TEFI retinal image scoring system above). Thesedata indicate the strain MRX050 may be useful for treating or preventinguveitis.

Example 2—Stability Testing

A composition described herein containing at least one bacterial straindescribed herein is stored in a sealed container at 25° C. or 4° C. andthe container is placed in an atmosphere having 30%, 40%, 50%, 60%, 70%,75%, 80%, 90% or 95% relative humidity. After 1 month, 2 months, 3months, 6 months, 1 year, 1.5 years, 2 years, 2.5 years or 3 years, atleast 50%, 60%, 70%, 80% or 90% of the bacterial strain shall remain asmeasured in colony forming units determined by standard protocols.

SEQUENCES(Eubacterium contortum partial 16S rRNA gene, type strain DSM 3982T,clone 1 - FR749945) SEQ ID NO: 1 1gatcctggct caggatgaac gctggcggcg tgcttaacac atgcaagtcg agcgaagcgc 61tttacttaga tttcttcgga ttgaagagtt ttgcgactga gcggcggacg ggtgagtaac 121gcgtgggtaa cctgcctcat acagggggat aacagttaga aatgactgct aataccgcat 181aagaccacgg taccgcatgg tacagtggga aaaactccgg tggtatgaga tggacccgcg 241tctgattagc tagttggtaa ggtaacggct taccaaggcg acgatcagta gccgacctga 301gagggtgacc ggccacattg ggactgagac acggcccaaa ctcctacggg aggcagcagt 361ggggaatatt gcacaatggg ggaaaccctg atgcagcgac gccgcgtgaa ggatgaagta 421tttcggtatg taaacttcta tcagcaggga agaaaatgac ggtacctgac taagaagccc 481cggctaacta cgtgccagca gccgcggtaa tacgtagggg gcaagcgtta tccggattta 541ctgggtgtaa agggagcgta gacggttatg taagtctgat gtgaaaaccc ggggctcaac 601cccgggactg cattggaaac tatgtaacta gagtgtcgga gaggtaagtg gaattcctag 661tgtagcggtg aaatgcgtag atattaggag gaacaccagt ggcgaaggcg gcttactgga 721cgatgactga cgttgaggct cgaaagcgtg gggagcaaac aggattagat accctggtag 781tccacgccgt aaacgatgaa tactaggtgt cgggtggcaa agccattcgg tgccgcagca 841aacgcaataa gtattccacc tggggagtac gttcgcaaga atgaaactca aaggaattga 901cggggacccg cacaagcggt ggagcatgtg gtttaattcg aagcaacgcg aagaacctta 961cctgctcttg acatccccct gaccggcgtg taatggtgcc tttccttcgg gacaggggag 1021acaggtggtg catggttgtc gtcagctcgt gtcgtgagat gttgggttaa gtcccgcaac 1081gagcgcaacc cttatcttta gtagccagcg gtttggccgg gcactctaga gagactgcca 1141gggataacct ggaggaaggt ggggatgacg tcaaatcatc atgcccctta tgagcagggc 1201tacacacgtg ctacaatggc gtaaacaaag ggaggcgaag ccgtgaggtg gagcaaatcc 1261caaaaataac gtctcagttc ggattgtagt ctgcaactcg actacatgaa gctggaatcg 1321ctagtaatcg cgaatcagaa tgtcgcggtg aatacgttcc cgggtcttgt acacaccgcc 1381cgtcacacca tgggagttgg taacgcccga agtcagtgac ccaaccgcaa ggagggagct 1441gccgaaggtg ggaccgataa ctggggtgaa gtcgtaacaa ggtagccgta tcggaaggtg 1501cggctggatc acctcctttc t(Eubacterium contortum partial 16S rRNA gene, type strain DSM 3982T,clone 2 - FR749946) SEQ ID NO: 2 1tttgatcctg gctcaggatg aacgctggcg acgtgcttaa cacatgcaag tcgagcgaag 61cactttactt tgatttcttc ggaatgaaag gttttgtgac tgagcggcgg acgggtgagt 121aacgcgtggg taacctgcct catacagggg gataacagtt agaaatgact gctaataccg 181cataagacca cagtaccgca tggtacagtg ggaaaaactc cggtggtatg agatggaccc 241gcgtctgatt agctagttgg taaggtaacg gcttaccaag gcgacgatca gtagccgacc 301tgagagggtg accggccaca ttgggactga gacacggccc aaactcctac gggaggcagc 361agtggggaat attgcacaat gggggaaacc ctgatgcagc gacgccgcgt gaaggatgaa 421gtatttcggt atgtaaactt ctatcagcag ggaagaaaat gacggtacct gactaagaag 481ccccggctaa ctacgtgcca gcagccgcgg taatacgtag ggggcaagcg ttatccggat 541ttactgggtg taaagggagc gtagacggtt atgtaagtct gatgtgaaaa cccggggctc 601aaccccggga ctgcattgga aactatgtaa ctagagtgtc ggagaggtaa gtggaattcc 661tagtgtagcg gtgaaatgcg tagatattag gaggaacacc agtggcgaag gcggcttact 721ggacgatgac tgacgttgag gctcgaaagc gtggggagca aacaggatta gataccctgg 781tagtccacgc cgtaaacgat gaatactagg tgtcgggtgg caaagccatt cggtgccgca 841gcaaacgcaa taagtattcc acctggggag tacgttcgca agaatgaaac tcaaaggaat 901tgacggggac ccgcacaagc ggtggagcat gtggtttaat tcgaagcaac gcgaagaacc 961ttacctgctc ttgacatccc cctgaccggc gtgtaatggt gcctttcctt cgggacaggg 1021gagacaggtg gtgcatggtt gtcgtcagct cgtgtcgtga gatgttgggt taagtcccgc 1081aacgagcgca acccttatct ttagtagcca gcggtttggc cgggcactct agagagactg 1141ccagggataa cctggaggaa ggtggggatg acgtcaaatc atcatgcccc ttatgagcag 1201ggctacacac gtgctacaat ggcgtaaaca aagggaggcg aagccgtgag gtggagcaaa 1261tcccaaaaat aacgtctcag ttcggattgt agtctgcaac tcgactacat gaagctggaa 1321tcgctagtaa tcgcgaatca gaatgtcgcg gtgaatacgt tcccgggtct tgtacacacc 1381gcccgtcaca ccatgggagt tggtaacgcc cgaagtcagt gacccaaccg caaggaggga 1441gctgccgagg gtgggaccga taactggggt gaagtcgtaa caaggtagcc gtatcggaag 1501gtgcggctgg atcacctcct ttct(Eubacterium contortum 16S ribosomal RNA ATCC 25540 - L34615)SEQ ID NO: 3 1nttttaacga gagtttgatc ctggctcagg atnaacgctg gcggcgtgct taacacatgc 61aagtcgagcg aagcrcttta cttwgatttc ttcggawtga arggttttgy gactgagcgg 121cggacgggtg agtaacgcgt gggtaacctg cctcatacag ggggataaca gttagaaatg 181actgctaata ccgcataaga ccacrgtacc gcatggtaca gtggnaaaaa ctccggtggt 241atgagatgga cccgcgtctg attagctagt tggtaaggta acggcttacn aaggcgacga 301tcagtagccg acctgagagg gtgaccggcc acattgggac tgagacacgg ccnnaactcc 361tacgggaggc agcagtgggg aatattgcac aatgggggaa accctgatgc agcgacgccg 421cgtgaaggat gaagtatttc ggtatgtaaa cttctatcag cagggaagaa aatgacggta 481cctgactaag aagccccggc taactacgtg ccagcagccn cggtaatacg tagggggnna 541gcgttatccg gatttactgg gtgtaaaggg agcgtagacg gttatgtaag tctgatgtga 601aaacccgggg ctcaaccccn nnnctgcatt ggaaactatg taactagagt gtcggagagg 661taagtggaat tcctagtgta gcggtgaaat gcgtagatat taggaggaac accagtggcg 721aaggcggctt actggacgat gactgacgtt gaggctcgaa agcgtgggga gcaaacagga 781ttagataccc tggtagtcca cgccgtaaac gatgaatact aggtgtcggg tggcaaagcc 841attcggtgcc gcagcaaacg caataagtat tccacctggg gagtacgttc gcaagaatga 901aactcaaagg aattgacggg naccngcaca agcggtggag catgtggttt aattcgaann 961aacgcgaaga accttacctg ctcttgacat ccccctgacc ggcgtgtaat ggtgccnttc 1021cttcgggaca ggggngacag gtggtgcatg gttgtcgtca gctcgtgtcg tgagatgttg 1081ggttaagtcc cnnaacgagc gcaaccctta tctttagtag ccagcggttt aggccggnna 1141ctctagagag actgccaggn ataacctgga ggaaggtggg gatgacgnnn aatcatcatg 1201ccccttatga gcaggnctac acacgtgcta caatggcgta aacaaaggga ggcgaagccg 1261ygaggtggag caaatcccaa aaataacgtc tcagttcgga ttgtagtctg caactcgact 1321acatgaagct ggaatcgcta gtaatcgcga atcagaatgt cgcggtgaat acgttcccnn 1381gtcttgtaca caccgnccgt cacaccatgg gagttggtaa cgcccgaagt cagtgaccca 1441accgcaagga gggagctgcc gaaggtggga ccgataactg ggg(consensus 16S rRNA sequence for Eubacterium contortum strain MRX050)SEQ ID NO: 4 TGCAGTCGAGCGAAGCAGCTTTACTTAGATTTCTTCGGATTGAAAGAGTTTTGCGACTGAGCGGCGGACGGGTGAGTAACGCGTGGGTAACCTGCCTCATACAGGGGGATAACAGTTAGAAATGACTGCTAATACCGCATAAGACCACGGTACCGCATGGTACAGTGGGAAAAACTCCGGTGGTATGAGATGGACCCGCGTCTGATTAGCTGGTTGGTAAGGTAACGGCTTACCAAGGCGACGATCAGTAGCCGACCTGAGAGGGTGACCGGCCACATTGGGACTGAGACACGGCCCAAACTCCTACGGGAGGCAGCAGTGGGGAATATTGCACAATGGGGGAAACCCTGATGCAGCGACGCCGCGTGAAGGATGAAGTATTTCGGTATGTAAACTTCTATCAGCAGGGAAGAAAATGACGGTACCTGACTAAGAAGCCCCGGCTAACTACGTGCCAGCAGCCGCGGTAATACGTAGGGGGCAAGCGTTATCCGGATTTACTGGGTGTAAAGGGAGCGTAGACGGTTATGTAAGTCTGATGTGAAAACCCGGGGCTCAACCCCGGGACTGCATTGGAAACTATGTAACTAGAGTGTCGGAGAGGTAAGTGGAATTCCTAGTGTAGCGGTGAAATGCGTAGATATTAGGAGGAACACCAGTGGCGAAGGCGGCTTACTGGACGATGACTGACGTTGAGGCTCGAAAGCGTGGGGAGCAAACAGGATTAGATACCCTGGTAGTCCACGCCGTAAACGATGAATACTAGGTGTCGGGTGGCAAAGCCATTCGGTGCCGCAGCAAACGCAATAAGTATTCCACCTGGGGAGTACGTTCGCAAGAATGAAACTCAAAGGAATTGACGGGGACCCGCACAAGCGGTGGAGCATGTGGTTTAATTCGAAGCAACGCGAAGAACCTTACCTGCTCTTGACATCCCCCTGACCGGCGCGTAATGGTGCCTTTCCTTCGGGACAGGGGAGACAGGTGGTGCATGGTTGTCGTCAGCTCGTGTCGTGAGATGTTGGGTTAAGTCCCGCAACGAGCGCAACCCTTATCTTTAGTAGCCAGCGGTATGGCCGGGCACTCTAGAGAGACTGCCAGGGATAACCTGGAGGAAGGTGGGGATGACGTCAAATCATCATGCCCCTTATGAGCAGGGCTACACACGTGCTACAATGGCGTAAACAAAGGGAGGCGAAGCCGCGAGGTGGAGCAAATCCCAAAAATAACGTCTCAGTTCGGATTGTAGTCTGCAACTCGACTACATGAAGCTGGAATCGCTAGTAATCGCGAATCAGAATGTCGCGGTGAATACGTTCCCGGGTCTTGTACACACCGCCCGTCACACCATGGGAGTTGGTAACGCCCGAAGTCAGTGACCCAACCGCAAGGAGGGAGCTGCCGAAG

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1.-30. (canceled)
 31. A method of treating a condition characterized byelevated levels of IL-17 in a subject as compared to a healthy subject,comprising administering to the subject a pharmaceutical compositionthat comprises at least 1×10³ CFU/g of a bacteria strain of the speciesEubacterium contortum with respect to total weight of the pharmaceuticalcomposition; and wherein the bacteria strain comprises a 16S rRNA genepolynucleotide, wherein the 16S rRNA gene polynucleotide comprises apolynucleotide sequence with at least 99% sequence identity to thepolynucleotide sequence of SEQ ID NO:4, as determined by aSmith-Waterman homology search algorithm using an affine gap search witha gap open penalty of 12, a gap extension penalty of 2, and a BlocksSubstitution Matrix (BLOSUM) of 62, and wherein the bacteria strain ispresent in an amount sufficient to reduce the levels of the IL-17 in thesubject, thereby treating the condition.
 32. The method of claim 31,wherein the bacteria strain is lyophilized.
 33. The method of claim 31,wherein the condition is selected from the group consisting of: uveitis;multiple sclerosis; a cancer; an arthritis; neuromyelitis optica;psoriasis; systemic lupus erythematosus; an inflammatory bowel disease;celiac disease; an asthma; allergic asthma; neutrophilic asthma; chronicobstructive pulmonary disease (COPD); scleritis; vasculitis; Behcet'sdisease; atherosclerosis; atopic dermatitis; emphysema; periodontitis;allergic rhinitis; and allograft rejection.
 34. The method of claim 33,wherein the condition is uveitis, and wherein the treating comprisesreducing retinal damage in uveitis.
 35. The method of claim 33, whereinthe condition is an arthritis.
 36. The method of claim 35, wherein thearthritis is rheumatoid arthritis, osteoarthritis, psoriatic arthritis,spondyloarthritis, ankylosing spondylitis, or juvenile idiopathicarthritis.
 37. The method of claim 33, wherein the condition is aninflammatory bowel disease, and wherein the inflammatory bowel diseaseis Crohn's disease or ulcerative colitis.
 38. The method of claim 33,wherein the condition is cancer, wherein the cancer is breast cancer,lung cancer, liver cancer, colon cancer, or ovarian cancer.
 39. Themethod of claim 31, wherein the pharmaceutical composition comprises apharmaceutically acceptable excipient, diluent, or carrier.
 40. Themethod of claim 39, wherein the pharmaceutically acceptable excipient,diluent, or carrier comprises a lyoprotectant.
 41. The method of claim31, wherein the pharmaceutical composition comprises from about 1×10⁶ toabout 1×10¹¹ CFU/g of the bacteria strain with respect to the totalweight of the pharmaceutical composition.
 42. The method of claim 31,wherein the bacteria strain comprises a 16S rRNA gene polynucleotide,wherein the 16S rRNA gene polynucleotide comprises a polynucleotidesequence with at least 99.5% sequence identity to the polynucleotidesequence of SEQ ID NO:4, as determined by a Smith-Waterman homologysearch algorithm using an affine gap search with a gap open penalty of12, a gap extension penalty of 2, and a Blocks Substitution Matrix(BLOSUM) of
 62. 43. The method of claim 31, wherein the bacteria straincomprises a 16S rRNA gene polynucleotide, wherein the 16S rRNA genepolynucleotide comprises a polynucleotide sequence that is thepolynucleotide sequence of SEQ ID NO:4.
 44. The method of claim 31,wherein the bacteria strain is strain MRX050 deposited with the NCIMBaccession number NCIMB
 42689. 45. The method of claim 31, wherein thesubject has the condition, or has been identified as being at risk ofthe condition.
 46. The method of claim 31, further comprisingadministering an additional therapeutic agent to the subject.
 47. Themethod of claim 31, wherein the pharmaceutical composition does notcontain an effective amount of any other bacteria strain.
 48. The methodof claim 31, wherein the IL-17 cytokine is selected from the groupconsisting of: IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F.
 49. Amethod of treating inflammation characterized by elevated levels ofIL-17 in a subject as compared to a healthy subject, comprisingadministering to the subject a pharmaceutical composition that comprisesat least 1×10⁶ CFU/g of a bacteria strain of the species Eubacteriumcontortum with respect to total weight of the pharmaceuticalcomposition, wherein the bacteria strain is present in an amountsufficient to reduce the levels of the IL-17 in the subject, therebytreating the inflammation.
 50. The method of claim 49, wherein thesubject has a condition selected from the group consisting of: uveitis;multiple sclerosis; a cancer; an arthritis; neuromyelitis optica;psoriasis; systemic lupus erythematosus; an inflammatory bowel disease;celiac disease; an asthma; allergic asthma; neutrophilic asthma; chronicobstructive pulmonary disease (COPD); scleritis; vasculitis; Behcet'sdisease; atherosclerosis; atopic dermatitis; emphysema; periodontitis;allergic rhinitis; and allograft rejection.